{"gene":"SRSF1","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":1990,"finding":"SF2/ASF (SRSF1) was purified to near homogeneity from HeLa cells as a ~33 kDa protein necessary for 5' splice site cleavage and lariat formation during pre-mRNA splicing in vitro. It is sufficient to complement an S100 fraction for splicing and appears required for assembly or stabilization of the earliest prespliceosome complex. The purified protein also carries RNA annealing activity.","method":"Protein purification to near homogeneity; in vitro splicing complementation assay; RNA annealing assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro splicing activity with near-homogeneous protein, multiple functional assays","pmids":["2145194"],"is_preprint":false},{"year":1995,"finding":"SELEX experiments with the RNA-binding domains of ASF/SF2 (SRSF1) and SC35 showed they recognize distinct purine-rich RNA motifs. Full-length protein binding assays confirmed the specificities are distinct and that the charged RS region is not a major specificity determinant for ASF/SF2. Cooperation between the two RBDs of ASF/SF2 determines binding specificity. An exonic splicing enhancer (ESE) containing three copies of a high-affinity ASF/SF2 binding site potently activates splicing in a manner that requires ASF/SF2 plus additional factors in S100 extracts.","method":"SELEX (in vitro RNA selection); RNA binding assays with full-length proteins; in vitro splicing assay in S100 extracts","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — SELEX plus binding assays plus functional splicing reconstitution, multiple orthogonal methods","pmids":["7543047"],"is_preprint":false},{"year":1997,"finding":"Both phosphorylation and dephosphorylation of ASF/SF2 (SRSF1) are required for pre-mRNA splicing in vitro. Phosphorylated ASF/SF2 complements SR-protein-deficient S100 extracts; unphosphorylated protein inhibits splicing. Thiophosphorylated (non-dephosphorylatable) ASF/SF2 supports spliceosome assembly but blocks the first transesterification reaction, demonstrating that dephosphorylation is required for the catalytic step.","method":"In vitro splicing assay; phosphorylation/dephosphorylation of recombinant ASF/SF2; thiophosphorylation to block dephosphorylation","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro splicing with biochemically defined phosphorylation states, multiple conditions tested","pmids":["9404896"],"is_preprint":false},{"year":1998,"finding":"Human DNA topoisomerase I (topo I) phosphorylates SF2/ASF (SRSF1) exclusively within the extended arginine-serine repeats of the RS domain. The N-terminal 174 amino acids of topo I are required for binding SF2/ASF; deletion of this region abolishes both binding and kinase activity. Kinase activity and SF2/ASF binding are tightly coupled; the C-terminal region of topo I contains the ATP-binding site.","method":"In vitro kinase assay; far-western blotting; fluorescence spectroscopy; deletion mutagenesis of topo I and SF2/ASF","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase reconstitution with mutagenesis and multiple binding assays, single lab","pmids":["9611241"],"is_preprint":false},{"year":1999,"finding":"The cellular protein p32 was co-purified with ASF/SF2 (SRSF1) and shown to interact directly with ASF/SF2 and SRp30c. p32 inhibits ASF/SF2 function as a splicing enhancer and splicing repressor by preventing stable RNA binding. p32 also inhibits phosphorylation of ASF/SF2 by HeLa nuclear extracts and specific SR kinases, placing p32 as a negative regulator that sequesters ASF/SF2 into an inhibitory complex.","method":"Co-purification; in vitro splicing assay; RNA binding assay; in vitro kinase assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple biochemical assays (co-purification, splicing, RNA binding, kinase), single lab","pmids":["10022843"],"is_preprint":false},{"year":1999,"finding":"SF2/ASF (SRSF1) controls alternative splicing of CD45 exon 4; its RRM domains (not the RS domain) are required for this skipping activity. Overexpression of SF2 induces CD45 exon 4 skipping in COS cells. SF2 is upregulated during T cell activation, coinciding with a shift from CD45RA to CD45RO isoform expression.","method":"Overexpression in COS cells; deletion mutant analysis; T cell activation assays; flow cytometry","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — overexpression with domain mutants and cellular readout, single lab","pmids":["10092085"],"is_preprint":false},{"year":2000,"finding":"SRPK1 co-expressed with ASF/SF2 in E. coli phosphorylates ASF/SF2 to a degree resembling native HeLa cell ASF/SF2. The E. coli-phosphorylated ASF/SF2 is functional in splicing and, unlike unphosphorylated protein, is soluble under native conditions, demonstrating that SRPK1 is a direct kinase for SRSF1.","method":"Co-expression in E. coli; in vitro splicing assay; protein solubility assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted phosphorylation and functional splicing in bacteria, clear biochemical readout","pmids":["10666475"],"is_preprint":false},{"year":2002,"finding":"ASF/SF2 (SRSF1) inhibits DNA relaxation by human topoisomerase I by interfering with the DNA cleavage and/or DNA binding steps of topoisomerase I catalysis. Inhibition correlates with direct interaction between the RS domain of ASF/SF2 and residues 208–735 of topoisomerase I. Phosphorylation of the RS domain reduces this inhibition.","method":"In vitro topoisomerase I relaxation assay; deletion mutant interaction mapping; phosphorylation experiments","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro biochemical assay with mutagenesis, single lab","pmids":["12270705"],"is_preprint":false},{"year":2002,"finding":"SF2/ASF (SRSF1) inhibits camptothecin-induced DNA cleavage by human topoisomerase I by reducing formation of the cleavable complex; this inhibition is independent of the phosphorylation status of SF2/ASF and does not result from SF2/ASF binding to DNA.","method":"In vitro topoisomerase I cleavage assay; camptothecin treatment; phosphorylation controls","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical assay, single lab, single method","pmids":["12135490"],"is_preprint":false},{"year":2005,"finding":"SF2/ASF (SRSF1) directly binds a splicing enhancer in exon 12 of the Ron tyrosine kinase receptor pre-mRNA and controls skipping of exon 11 to generate constitutively active DeltaRon. Overexpression and RNAi of SF2/ASF demonstrate it directly controls epithelial-to-mesenchymal transition and cell motility through DeltaRon isoform production. Knockdown of DeltaRon mRNA reverses the motility effect of SF2/ASF overexpression.","method":"RNA binding assay; overexpression and RNAi; RT-PCR splicing assay; cell motility assay; epistasis by DeltaRon knockdown","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated, RNAi epistasis rescue experiment, multiple orthogonal methods","pmids":["16364913"],"is_preprint":false},{"year":2005,"finding":"Crystal structure of SRPK1 bound to an SR-protein peptide identified a docking motif in ASF/SF2 (SRSF1). This docking motif restricts SRPK1-mediated phosphorylation to the N-terminal portion of the RS domain, which is essential for assembly of ASF/SF2 into nuclear speckles. Clk/Sty kinase subsequently phosphorylates the C-terminal portion of the RS domain, causing release of ASF/SF2 from speckles. Sequential phosphorylation by SRPK1 then Clk/Sty thus controls subcellular localization.","method":"Crystal structure; in vitro kinase assay with deletion mutants; subcellular localization by immunofluorescence; docking motif mutagenesis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and functional localization assay, multiple orthogonal methods","pmids":["16209947"],"is_preprint":false},{"year":2006,"finding":"SRp30a (SRSF1) regulates the alternative splicing of caspase-9 pre-mRNA: its downregulation by RNAi increases the antiapoptotic caspase-9b isoform and decreases the proapoptotic caspase-9a isoform. SRp30a is also required for ceramide to induce inclusion of the exon 3/4/5/6 cassette of caspase-9.","method":"RNAi knockdown; RT-PCR splicing assay; ceramide treatment","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with specific splicing readout and signal pathway perturbation, single lab","pmids":["16505493"],"is_preprint":false},{"year":2007,"finding":"NMR structure of RRM2 of SF2/ASF (SRSF1) revealed that RRM2 binds RNA using a conserved SWQLKD tryptophan on helix α1 combined with strand β2 residues and a histidine on loop 5 — a novel RNA-binding mode. The linker connecting RRM1 and RRM2 contains arginine residues that form a binding site for the mRNA export factor TAP; TAP binding to this linker displaces RNA bound to RRM2.","method":"NMR structure determination; RNA binding assay; TAP binding assay with competition experiment","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure plus functional binding validation, single lab but two orthogonal approaches","pmids":["17668007"],"is_preprint":false},{"year":2007,"finding":"SF2/ASF (SRSF1) overexpression transforms immortal rodent fibroblasts that form sarcomas in nude mice; transformation is driven in part by alternative splicing of BIN1 (generating isoforms lacking tumor-suppressor activity), MNK2 (producing an isoform with MAP kinase-independent eIF4E phosphorylation), and S6K1 (producing an oncogenic isoform). Knockdown of SF2/ASF or the oncogenic S6K1 isoform reverses transformation in vitro and in vivo.","method":"Overexpression transformation assay; nude mouse xenograft; shRNA knockdown; RT-PCR splicing; epistasis by S6K1 isoform knockdown","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo transformation with multiple splice-target validations and rescue experiments, replicated across targets","pmids":["17310252"],"is_preprint":false},{"year":2008,"finding":"CLIP-seq of SFRS1 (SRSF1) in human embryonic kidney cells identified 23,632 binding sites across diverse RNA classes (mRNA, miRNA, snoRNA, ncRNA) sharing a purine-rich consensus motif. SFRS1-bound sequences are enriched near splice sites. mRNAs encoding RNA processing factors are significantly over-represented among SFRS1 targets.","method":"CLIP-seq (cross-linking immunoprecipitation and high-throughput sequencing); motif analysis","journal":"Genome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide CLIP-seq with motif validation, single lab","pmids":["19116412"],"is_preprint":false},{"year":2008,"finding":"SF2/ASF (SRSF1) overexpression activates the mTORC1 branch of the mTOR pathway, measured by S6K and 4EBP1 phosphorylation, without activating Akt (mTORC2 substrate). mTORC1 activation bypasses upstream PI3K/Akt signaling and is essential for SF2/ASF-mediated transformation; rapamycin blocks transformation in vitro and in vivo.","method":"Phosphorylation immunoblot; shRNA knockdown of mTOR, Raptor, Rictor; rapamycin inhibition; focus formation and xenograft assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple genetic and pharmacological perturbations with specific pathway readouts, in vitro and in vivo","pmids":["18832178"],"is_preprint":false},{"year":2010,"finding":"SF2/ASF (SRSF1) negatively autoregulates its own expression through multiple post-transcriptional and translational mechanisms. Unproductive alternative splicing (generating NMD-sensitive isoforms) accounts for part of the autoregulation. The primary mechanism is translational repression mediated by RRM2 and the ultraconserved 3'UTR. Overexpression shifts the target mRNA toward monoribosomes. Translational repression is partly independent of Dicer and 5' cap.","method":"RT-PCR isoform analysis; polysome fractionation; mutagenesis of RRM2 and 3'UTR; Dicer knockdown","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (isoform analysis, polysome profiling, mutagenesis), single lab","pmids":["20139984"],"is_preprint":false},{"year":2010,"finding":"SF2/ASF (SRSF1) directly interacts with the primary miR-7 transcript (pri-miR-7) to facilitate Drosha cleavage, promoting miR-7 maturation independently of its splicing function. Mature miR-7 in turn targets the 3'UTR of SF2/ASF to repress its translation, forming a negative feedback loop. Similar regulation may apply to miR-221 and miR-222.","method":"miRNA deep sequencing; RNA immunoprecipitation; Drosha cleavage assay; 3'UTR reporter assay; overexpression and knockdown","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RIP, functional Drosha assay, reporter assay — multiple orthogonal methods, single lab","pmids":["20385090"],"is_preprint":false},{"year":2010,"finding":"SF2/ASF (SRSF1) is a regulator of the SUMO conjugation pathway: overexpression stimulates and knockdown inhibits global SUMO conjugation. SRSF1 interacts with the SUMO E2 enzyme Ubc9 and the E3 ligase PIAS1, and RRM2 is necessary and sufficient for sumoylation enhancement. SRSF1 promotes sumoylation of RNA processing factors and is involved in heat-shock-induced sumoylation.","method":"Co-immunoprecipitation; overexpression and knockdown; in vitro and in vivo sumoylation assay; domain deletion analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vivo and in vitro sumoylation, domain mapping — multiple orthogonal methods, single lab","pmids":["20805487"],"is_preprint":false},{"year":2010,"finding":"SRSF1 overexpression in NSCLC cells promotes survival by binding survivin mRNA, enhancing its translation through an mTORC1/4E-BP1-dependent mechanism, and increasing survivin mRNA stability. SRSF1 knockdown reduces survivin protein and induces apoptosis.","method":"RNA immunoprecipitation; mTORC1 inhibition (rapamycin); siRNA knockdown; western blot; mRNA stability assay","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and functional pharmacological inhibition, single lab, two orthogonal methods","pmids":["20682707"],"is_preprint":false},{"year":2010,"finding":"Akt phosphorylates SRSF1 (SRp30a) at serines 199, 201, 227, and 234 via the PI3K/Akt pathway, mediating exclusion of the exon 3/4/5/6 cassette of caspase-9 pre-mRNA to produce antiapoptotic caspase-9b in NSCLC cells.","method":"PI3K/Akt inhibition; phosphorylation mapping by site-directed mutagenesis; RT-PCR splicing assay; EGFR overexpression/mutation models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation site mutagenesis with functional splicing readout, pathway inhibition, single lab","pmids":["21045158"],"is_preprint":false},{"year":2011,"finding":"SRSF1 is hyperphosphorylated in response to chronic replication-dependent DNA damage (ATM activation) in 46BR.1G1 cells; this hyperphosphorylation is partially prevented by ATM inhibitor caffeine. Hyperphosphorylation of SRSF1 alters its subnuclear distribution and shifts the alternative splicing of target genes.","method":"Proteomic phosphorylation analysis; ATM inhibition; immunofluorescence subnuclear localization; RT-PCR splicing assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus localization and functional splicing readout, single lab","pmids":["21984412"],"is_preprint":false},{"year":2012,"finding":"SRSF1 overexpression in mammary epithelial cells promotes alternative splicing of BIM and BIN1 to generate isoforms lacking pro-apoptotic functions, contributing to increased proliferation and delayed apoptosis. These oncogenic effects require RRM1 and nuclear functions of SRSF1. SRSF1 cooperates specifically with MYC to transform mammary epithelial cells, in part by potentiating eIF4E activation.","method":"Overexpression in MCF-10A and COMMA-1D cells; orthotopic transplantation; 3D culture; RT-PCR splicing; domain deletion analysis; MYC co-expression","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo orthotopic tumor model, 3D culture, domain mutagenesis, epistasis with MYC — multiple orthogonal methods, replicated","pmids":["22245967"],"is_preprint":false},{"year":2012,"finding":"MYC directly activates transcription of SRSF1 through two non-canonical E-boxes in its promoter. Increased SRSF1 downstream of MYC is sufficient to modulate alternative splicing of MKNK2 and TEAD1. SRSF1 knockdown reduces MYC oncogenic activity (proliferation, anchorage-independent growth).","method":"Chromatin immunoprecipitation (ChIP); promoter reporter assay; MYC knockdown; SRSF1 knockdown; RT-PCR splicing assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP, promoter reporter, and functional KD with splicing readout — multiple orthogonal methods, single lab","pmids":["22545246"],"is_preprint":false},{"year":2012,"finding":"SRSF1 is a necessary component of an MDM2/RPL5 ribosomal protein complex (separate from the ribosome) that stabilizes p53 by abrogating MDM2-dependent proteasomal degradation. Increased SRSF1 expression in primary human fibroblasts induces p53-dependent oncogene-induced senescence (OIS), implicating RPL5-MDM2 complex in OIS.","method":"Co-immunoprecipitation; p53 stability assay; SRSF1 overexpression in primary fibroblasts; senescence assays (SA-β-gal); MDM2 inhibition controls","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP of endogenous complex, functional OIS readout, pathway epistasis — multiple orthogonal methods, single lab","pmids":["23478443"],"is_preprint":false},{"year":2012,"finding":"SRSF1 depletion in human cells compromises association of splicing factors with nuclear speckles and influences levels/activity of other SR proteins. SRSF1, together with lncRNA MALAT1, can nucleate assembly of nuclear speckles. On a stably integrated reporter gene locus, SRSF1 promotes RNA Pol II-mediated transcription.","method":"siRNA knockdown; immunofluorescence of nuclear speckle markers; reporter gene assay with stable integration; FRAP-like analysis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with localization readout and reporter gene assay, single lab","pmids":["22855529"],"is_preprint":false},{"year":2013,"finding":"SRSF1 directly controls alternative splicing of fibronectin EDA exon inclusion in human primary endometrial fibroblasts; RNAi knockdown of SRSF1 reduces EDA+ fibronectin, and higher SRSF1 expression in endometrium is linked to stronger EDA exon inclusion and consequently greater trophoblast invasion capacity in co-culture assay.","method":"RNAi; RT-PCR splicing assay; co-culture invasion assay; quantitative protein expression analysis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with splicing readout and functional invasion assay, single lab","pmids":["23966470"],"is_preprint":false},{"year":2014,"finding":"HIV-1 transcription factor SRSF1 and Tat recognize overlapping sequences within TAR RNA and 7SK RNA. SRSF1 can increase basal HIV-1 transcription in the absence of Tat by recruiting P-TEFb to TAR from the 7SK snRNP, and can inhibit Tat transactivation by directly competing for TAR binding.","method":"RNA binding competition assay; Tat transactivation reporter assay; co-immunoprecipitation with 7SK snRNP components; overexpression/knockdown","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding competition and transcription reporter, single lab","pmids":["25416801"],"is_preprint":false},{"year":2014,"finding":"SRSF1 binds to CD6 intron 4 and activates exon 5 splicing (promoting exon 5 inclusion). During T cell activation, SRSF1 levels decrease, its recruitment to the CD6 transcript is impaired by increased chromatin acetylation, and this leads to exon 5 skipping generating CD6Δd3, which no longer localizes at the immunological synapse.","method":"RNA immunoprecipitation; chromatin immunoprecipitation; HDAC inhibitor treatment; overexpression/knockdown; RT-PCR","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and ChIP with functional localization readout, single lab","pmids":["24890719"],"is_preprint":false},{"year":2015,"finding":"RNA-seq in 3D MCF-10A cultures identified hundreds of SRSF1-regulated alternative splicing events. De novo motif discovery reconciled previous discrepancies. Bayesian positional modeling showed that SRSF1 binding near the 5' splice site generally promotes exon inclusion, whereas binding near the 3' splice site promotes either skipping or inclusion. Overexpression of an SRSF1-regulated exon-9-included CASC4 isoform partially recapitulates SRSF1's oncogenic effects.","method":"RNA-seq; de novo motif discovery; Bayesian positional model; RT-PCR validation; CASC4 isoform overexpression in 3D culture","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide RNA-seq with computational modeling and functional validation of a downstream target, multiple orthogonal methods","pmids":["26431027"],"is_preprint":false},{"year":2017,"finding":"SRSF1 promotes vascular smooth muscle cell (VSMC) proliferation by favoring production of the truncated p53 isoform Δ133p53. Δ133p53 transcriptionally activates KLF5 via a Δ133p53-EGR1 complex, accelerating cell-cycle progression. SMC-specific Srsf1 knockout mice develop less intimal thickening after wire injury, and Srsf1 overexpression in rat arteries enhances neointima formation.","method":"Conditional SMC-specific knockout mouse; wire injury model; adenoviral overexpression; immunoprecipitation of Δ133p53-EGR1 complex; siRNA knockdown; cell proliferation assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO and overexpression with mechanistic complex IP, multiple orthogonal methods","pmids":["28799539"],"is_preprint":false},{"year":2017,"finding":"Depletion of SRSF1 specifically prevents nuclear export of pathological C9ORF72 repeat-containing transcripts via the NXF1 pathway, suppressing dipeptide repeat protein production and neurodegeneration in Drosophila and patient-derived neurons. Preventing the interaction of SRSF1 with NXF1 also inhibits this export and alleviates neurotoxicity.","method":"SRSF1 depletion in Drosophila (genetic); patient-derived motor neuron co-culture; SRSF1-NXF1 interaction disruption; nuclear/cytoplasmic fractionation; repeat RNA export assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo Drosophila model, patient-derived neurons, mechanistic interaction disruption — replicated across systems","pmids":["28677678"],"is_preprint":false},{"year":2018,"finding":"SRSF1 stimulates nonsense-mediated mRNA decay (NMD) by increasing UPF1 binding to mRNAs while in or associated with the nucleus, bypassing UPF2 recruitment. SRSF1 acts downstream of a PTC in a manner analogous to the EJC, and splicing/EJC deposition enhances the SRSF1-mediated NMD effect.","method":"RNA immunoprecipitation; tethering assay; NMD reporter assay; UPF2 depletion; EJC depletion; endogenous PTC-containing transcript analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RIP, reporter tethering, and multiple depletion experiments, single lab with multiple orthogonal methods","pmids":["29768215"],"is_preprint":false},{"year":2018,"finding":"SRSF1 binds to LIG1 mRNA and regulates LIG1 expression by increasing mRNA stability and enhancing translation in an mTOR-dependent manner in NSCLC cells.","method":"RNA immunoprecipitation; mRNA stability assay; mTOR inhibition (rapamycin); siRNA knockdown; western blot","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and functional mRNA stability/translation assays, single lab","pmids":["30181552"],"is_preprint":false},{"year":2018,"finding":"NMR spectroscopy identified two electrostatic residues in helix α2 and a hydrophobic residue in helix α1 of RRM1 of SRSF1 as the binding surface for protein phosphatase 1 (PP1). Mutations in these residues dissociate SRSF1 from PP1, enhance phosphatase activity, reduce RS domain phosphorylation, shift alternative splicing patterns, and increase SRSF1 diffusion from speckles to the nucleoplasm.","method":"NMR spectroscopy; site-directed mutagenesis; in vitro dephosphorylation assay; FRAP (diffusion from speckles); RT-PCR splicing assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with mutagenesis, functional phosphatase assay, and localization/splicing readouts — multiple orthogonal methods","pmids":["30185622"],"is_preprint":false},{"year":2019,"finding":"SRSF1 controls alternative splicing of MYO1B to produce membrane-localized oncogenic MYO1B-fl isoform in glioma. SRSF1-guided AS of MYO1B activates PDK1/AKT and PAK/LIMK pathways to promote cell proliferation, survival, and invasion.","method":"RNA-seq; RT-PCR splicing assay; siRNA knockdown; MYO1B-fl overexpression; pathway inhibition; xenograft model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RNA-seq, splicing validation, pathway epistasis, in vivo model — multiple orthogonal methods, single lab","pmids":["30481162"],"is_preprint":false},{"year":2019,"finding":"T cell-restricted Srsf1-deficient mice develop systemic autoimmunity; T cells show reduced PTEN expression and increased mTORC1 activity. mTORC1 inhibitor rapamycin suppresses proinflammatory cytokine production and autoimmunity in Srsf1-deficient mice. SRSF1 overexpression restores PTEN and suppresses mTORC1 activation, establishing an SRSF1–PTEN–mTORC1 axis in T cells.","method":"T cell-conditional Srsf1 knockout mouse; flow cytometry; immunoblot of PTEN and mTORC1 targets; rapamycin treatment; SRSF1 overexpression rescue","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse with mechanistic pathway rescue, pharmacological epistasis, replicated in patient samples","pmids":["31487268"],"is_preprint":false},{"year":2020,"finding":"AMP-activated protein kinase (AMPK) directly phosphorylates SRSF1 at Ser133 within RRM. Ser133 phosphorylation suppresses SRSF1 interaction with specific RNA sequences without altering subcellular localization, and AMPK-dependent phosphorylation of SRSF1 regulates alternative splicing of Ron pre-mRNA by suppressing SRSF1 binding to exon 12.","method":"In vitro kinase assay; site-directed mutagenesis (S133A); RNA-protein interaction assay; RT-PCR splicing assay; subcellular fractionation","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase reconstitution with phosphosite mutagenesis and functional RNA-binding/splicing readouts, single lab","pmids":["32453427"],"is_preprint":false},{"year":2021,"finding":"NMR and structural analysis of SRSF1 RRM1 revealed that it binds preferentially to a CN motif (C followed by any nucleotide). The flexible inter-RRM linker allows RRM1 to bind RNA on both sides of the RRM2 binding site (bimodal interaction mode). An E87N mutation in RRM1 engineered from this structure enables binding to uridines and activates SMN exon 7 inclusion.","method":"NMR structure determination; RNA binding assay; site-directed mutagenesis (E87N); splicing assay (SMN exon 7 inclusion)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with mutagenesis and functional splicing validation, structure-function relationship established","pmids":["33462199"],"is_preprint":false},{"year":2021,"finding":"SRSF1 depletion prevents R-loop formation in hepatocytes; SRSF1 loss causes excessive RNA-DNA hybrids, induces DNA damage, globally inhibits mRNA transcription and protein synthesis, impairs lipid metabolism/trafficking, and leads to necroptotic cell death with NASH-like liver pathology in mice. These effects are reproduced in SRSF1-depleted human liver cancer cells.","method":"Hepatocyte-specific conditional Srsf1 knockout mouse; R-loop immunofluorescence (S9.6 antibody); transcriptome and proteome sequencing; RNA binding analysis (eCLIP); liver pathology","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse with transcriptome/proteome/CLIP multi-omics, in vivo and human cell validation","pmids":["36759613"],"is_preprint":false},{"year":2021,"finding":"SRSF1 nuclear retention (via knock-in NRS) in mice causes small body size, hydrocephalus, and immotile sperm due to ciliary defects. Nuclear-retained SRSF1 reduces translation of a subset of mRNAs and decreases abundance of proteins involved in multiciliogenesis, disrupting ciliary ultrastructure and motility, demonstrating that cytoplasmic shuttling of SRSF1 is required for ciliogenesis.","method":"Genome editing (knock-in NRS); mouse developmental phenotyping; polysome/translation assay; proteomics; electron microscopy of cilia","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — knock-in mouse model with multiple orthogonal readouts (proteomics, translation, electron microscopy), direct mechanistic link to shuttling","pmids":["34338635"],"is_preprint":false},{"year":2021,"finding":"A single molecule of SRSF1 can be recruited by a U1 snRNP independently of exon sequences. Structural and cross-linking data show SRSF1 contacts U1 snRNA stem-loop 3. This exon-independent recruitment is proposed to underlie exon definition by U1 snRNP.","method":"Single-molecule fluorescence; structural NMR/cross-linking analysis; mutagenesis of stem-loop 3","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — single-molecule methods combined with structural cross-linking and mutagenesis, single lab with multiple orthogonal approaches","pmids":["34779515"],"is_preprint":false},{"year":2021,"finding":"SRSF1 conditional deletion in T cells causes T cell lymphopenia with increased apoptosis and decreased expression of anti-apoptotic Bcl-xL. SRSF1 overexpression rescues T cell survival from SLE patients, establishing a direct role for SRSF1 in controlling Bcl-xL expression and T cell homeostasis.","method":"Conditional Srsf1 KO mouse; flow cytometry (apoptosis); quantitative PCR and immunoblot of Bcl-xL; SRSF1 overexpression rescue in human T cells","journal":"Rheumatology (Oxford, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with mechanistic rescue, single lab","pmids":["32206811"],"is_preprint":false},{"year":2021,"finding":"SRSF1 inhibits autophagosome formation by (1) promoting splicing of Bcl-xL long isoform which binds Beclin1 and dissociates the Beclin1-PIK3C3 complex, and (2) directly interacting with PIK3C3 to disrupt Beclin1-PIK3C3 interaction. SRSF1 itself is degraded by starvation/oxidative stress-induced autophagy through interaction with LC3-II, creating a positive feedback loop.","method":"Co-immunoprecipitation; siRNA knockdown; LC3-II autophagy markers; RT-PCR splicing assay; starvation and oxidative stress assays; xenograft model","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP showing direct PIK3C3 binding, splicing assay, multiple functional readouts, in vivo model","pmids":["33664238"],"is_preprint":false},{"year":2021,"finding":"SRSF1 directly binds MALAT1 lncRNA and facilitates its RNA stability in glioma cells. SRSF1 is the most highly expressed SRSF in 9 tumor types, and it regulates the cell cycle in glioma by stabilizing NEAT1 lncRNA through direct binding.","method":"RNA immunoprecipitation; RNA stability assay; SRSF1 knockdown; NEAT1 knockdown cell cycle analysis","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and RNA stability assay, single lab","pmids":["31200124"],"is_preprint":false},{"year":2021,"finding":"SRSF1 directly binds and promotes export of NKILA lncRNA via clustered SRSF1/SRSF7 binding sites in CAR-N region, facilitating TREX/UAP56/ALYREF assembly and TAP-dependent nuclear export; NKILA lacking CAR-N is unable to inhibit breast cancer cell migration.","method":"RNA pull-down; mass spectrometry; siRNA screening; EMSA; RNA and protein immunoprecipitation; knock-in models","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods (MS, EMSA, RIP), knock-in validation, single lab","pmids":["34096602"],"is_preprint":false},{"year":2021,"finding":"SRPK1/2 phosphorylate SRSF1, promoting its nuclear translocation, and PP1α opposes this by dephosphorylating SRSF1. The balance of SRSF1 phosphorylation/subcellular localization by SRPK1/2 and PP1α controls alternative splicing of MKNK2 in colon adenocarcinoma cells, with high nuclear SRSF1 promoting MKNK2b (oncogenic) isoform.","method":"Immunohistochemistry; western blot; siRNA knockdown; RT-PCR splicing assay; xenograft model; phosphorylation analysis","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic manipulation of kinase/phosphatase with splicing readout and subcellular localization, single lab","pmids":["33602301"],"is_preprint":false},{"year":2021,"finding":"SRSF1 conditional deletion in thymocytes blocks the transition of immature TCRβhi thymocytes to mature ones. SRSF1 directly binds and regulates alternative splicing of Irf7 and Il27ra in response to type I interferon signaling; forced IRF7 expression rectifies the maturation defects of SRSF1-deficient thymocytes.","method":"Conditional Srsf1 KO mouse; flow cytometry; RNA-seq; SRSF1-RNA binding assay; IRF7 rescue overexpression","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO, RNA-seq, direct binding assay, genetic rescue — multiple orthogonal methods, single lab","pmids":["33863728"],"is_preprint":false},{"year":2021,"finding":"Conditional deletion of SRSF1 in Treg cells causes profound autoimmunity; mechanistically, loss of SRSF1 elevates glycolytic metabolism and mTORC1 activity, and increases proinflammatory cytokine production, controlling Treg cell plasticity.","method":"Treg-specific Srsf1 conditional KO mouse; flow cytometry; metabolic assays (glycolysis); mTORC1 pathway immunoblot; cytokine measurement","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with metabolic and signaling pathway readouts, single lab","pmids":["34233194"],"is_preprint":false},{"year":2021,"finding":"The RNA binding protein RNPS1, when overexpressed, suppresses DNA fragmentation, hypermutation, and G2 arrest caused by ASF/SF2 (SRSF1) depletion. This suggests RNPS1 functions together with ASF/SF2 to form RNP complexes on nascent transcripts and prevent R-loop formation; ASF/SF2 depletion does not affect RNPS1 expression, and RNPS1 cannot compensate for ASF/SF2 splicing function.","method":"RNAi depletion; RNPS1 overexpression suppressor experiment; DNA damage assays (HMW fragmentation, mutation frequency); cell cycle analysis","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic suppressor experiment with defined cellular phenotypes, single lab","pmids":["17959926"],"is_preprint":false},{"year":2023,"finding":"PRMT1 methylates SRSF1; this methylation is critical for SRSF1 phosphorylation, SRSF1 binding to RNA, and exon inclusion. PRMT1 overexpression in breast tumors correlates with increased SRSF1 arginine methylation and aberrant exon inclusion. A selective PRMT1 inhibitor (iPRMT1) suppresses SRSF1 methylation, exon inclusion, and breast cancer cell growth; combination with SRSF1 phosphorylation inhibitors shows additive growth suppression.","method":"PRMT1 methylome profiling; in vitro methylation assay; RNA binding assay; RT-PCR splicing; pharmacological inhibition (iPRMT1, SRPK inhibitor); cell proliferation assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro methylation reconstitution with RNA binding assay, pharmacological manipulation, single lab multiple methods","pmids":["37938975"],"is_preprint":false},{"year":2023,"finding":"SRSF1 activates MAPK signaling in pancreas by upregulating IL1R1 through alternative-splicing-regulated mRNA stability. In phenotypically normal epithelial cells expressing KRASG12D, SRSF1 protein is destabilized through a negative feedback mechanism. Hyperactive MYC overcomes this feedback, facilitating PDAC tumorigenesis. Increased SRSF1 is sufficient to induce pancreatitis and accelerate KRASG12D-mediated PDAC.","method":"Conditional transgenic/KO mouse models; pancreas organoids; RNA-seq; RT-PCR; mRNA stability assay; MAPK pathway immunoblot","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple mouse models, organoids, mechanistic pathway validation with multiple orthogonal methods","pmids":["37098965"],"is_preprint":false},{"year":2023,"finding":"Haploinsufficiency of SRSF1 causes a syndromic neurodevelopmental disorder. Loss-of-function and pathogenic missense variants impair SRSF1 splicing activity as demonstrated by in vivo splicing assay in Drosophila, and correlate with a detectable DNA methylation episignature in blood-derived DNA from affected individuals.","method":"In vivo Drosophila splicing assay; in silico structural modeling; DNA methylation episignature analysis; genotype-phenotype analysis in 17 individuals","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo Drosophila functional assay with orthogonal epigenetic confirmation, single study","pmids":["37071997"],"is_preprint":false},{"year":2023,"finding":"RNF125 E3 ubiquitin ligase physically interacts with SRSF1 (identified by mass spectrometry and co-immunoprecipitation) and accelerates proteasome-mediated degradation of SRSF1, thereby inhibiting the SRSF1/ERK signaling pathway and suppressing HCC proliferation and metastasis.","method":"Mass spectrometry; co-immunoprecipitation; ubiquitin ladder assay; proteasome inhibition; siRNA/overexpression; xenograft model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, and functional rescue, single lab","pmids":["37142680"],"is_preprint":false},{"year":2024,"finding":"SRSF1 physically interacts with FANCD2 (identified by Co-IP); SRSF1 stimulates FANCD2 monoubiquitination in an RNA-dependent fashion. FANCD2 monoubiquitination is required for assembly of the SRSF1-NXF1 nuclear export complex and mRNA export. Cancer-associated SRSF1 mutants fail to interact with FANCD2, leading to deficient FANCD2 monoubiquitination, decreased mRNA export, and R-loop accumulation.","method":"Co-immunoprecipitation; monoubiquitination assay; mRNA export assay; R-loop detection (S9.6); SRSF1 cancer mutant analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, functional ubiquitination and export assays, mutant analysis — multiple orthogonal methods, single lab","pmids":["38165804"],"is_preprint":false}],"current_model":"SRSF1 (SF2/ASF) is a multifunctional SR protein whose RS domain phosphorylation state (controlled sequentially by SRPK1, Clk/Sty, AMPK, Akt, and PP1α, and additionally by arginine methylation via PRMT1) governs its assembly into nuclear speckles, RNA-binding specificity, and activity in splicing; its two RRMs recognize purine-rich ESEs and CN motifs to promote exon inclusion or skipping in a position-dependent manner, while the inter-RRM linker engages the mRNA export factor NXF1/TAP; beyond splicing, SRSF1 shuttles to the cytoplasm to regulate mRNA stability and translation (including mTORC1-dependent translation), facilitates miRNA maturation via Drosha, promotes NMD by recruiting UPF1 downstream of PTCs, suppresses R-loop formation to maintain genome integrity, acts as a SUMO E3-like ligase by interacting with Ubc9 and PIAS1, stabilizes p53 by engaging the RPL5-MDM2 complex, and is subject to ubiquitin-mediated proteasomal degradation by RNF125, with its haploinsufficiency causing a neurodevelopmental syndrome and its overexpression driving oncogenesis through multiple downstream splicing targets including S6K1, MNK2, BIN1, Ron/DeltaRon, caspase-9, and MYO1B."},"narrative":{"mechanistic_narrative":"SRSF1 (SF2/ASF) is a prototypical SR protein that functions as an essential pre-mRNA splicing factor, originally purified as a ~33 kDa activity required for 5' splice site cleavage, lariat formation, and assembly of the earliest prespliceosome complex [PMID:2145194]. Its two RRMs recognize purine-rich exonic splicing enhancers and CN motifs through a cooperative, bimodal binding mode, with RRM2 employing a noncanonical surface and the flexible inter-RRM linker permitting RNA engagement on both sides of the RRM2 site [PMID:7543047, PMID:17668007, PMID:33462199]; genome-wide binding and positional modeling established that SRSF1 occupancy near the 5' splice site promotes exon inclusion whereas 3'-proximal binding can drive skipping or inclusion [PMID:19116412, PMID:26431027]. SRSF1 activity is governed by the phosphorylation state of its RS domain: SRPK1/2 phosphorylate the N-terminal RS region to drive nuclear-speckle assembly and nuclear translocation, Clk/Sty phosphorylates the C-terminal RS region to release it from speckles, and PP1—docked on RRM1—dephosphorylates it, with both phosphorylation and subsequent dephosphorylation being required across the splicing cycle [PMID:9404896, PMID:16209947, PMID:30185622, PMID:33602301]; additional control comes from AMPK and Akt phosphorylation within the RRM and from PRMT1-mediated arginine methylation, which together tune RNA binding and splice-target selection [PMID:21045158, PMID:32453427, PMID:37938975]. Beyond nuclear splicing, SRSF1 shuttles to the cytoplasm to regulate mRNA stability and translation, including mTORC1-dependent translation, and this shuttling is required for ciliogenesis [PMID:20139984, PMID:34338635]; it engages the mRNA export factor NXF1/TAP via its inter-RRM linker, a complex whose assembly depends on SRSF1-stimulated FANCD2 monoubiquitination and which is exploited for pathological C9ORF72 repeat-RNA export [PMID:17668007, PMID:28677678, PMID:38165804]. SRSF1 additionally promotes miR-7 maturation via Drosha, stimulates UPF1-dependent nonsense-mediated decay, suppresses R-loop formation to protect genome integrity, and acts as a SUMO pathway regulator interacting with Ubc9 and PIAS1 [PMID:20385090, PMID:29768215, PMID:36759613, PMID:20805487]. Acting downstream of MYC, which transcriptionally activates it, SRSF1 is a potent oncoprotein whose overexpression transforms cells through splicing of targets including BIN1, MNK2, S6K1, Ron, caspase-9, and MYO1B and through mTORC1 activation, while it conversely enforces p53-dependent senescence via the RPL5-MDM2 complex and is degraded by the E3 ligase RNF125 [PMID:17310252, PMID:22545246, PMID:18832178, PMID:22245967, PMID:23478443, PMID:37142680]. SRSF1 is also essential for T-cell homeostasis and immune tolerance through an SRSF1-PTEN-mTORC1 axis [PMID:31487268]. Haploinsufficiency of SRSF1 causes a syndromic neurodevelopmental disorder with a defined DNA methylation episignature [PMID:37071997].","teleology":[{"year":1990,"claim":"Established SRSF1 as a bona fide splicing factor by showing a purified ~33 kDa protein is necessary and sufficient to reconstitute early spliceosome assembly and 5' splice site usage, defining the core activity all later work builds on.","evidence":"Protein purification to near homogeneity with in vitro splicing complementation and RNA annealing assays in HeLa extracts","pmids":["2145194"],"confidence":"High","gaps":["Did not define the RNA sequence specificity","Did not assign roles to individual domains"]},{"year":1995,"claim":"Defined the RNA-recognition logic by showing SRSF1's RRMs cooperatively bind a distinct purine-rich motif and that high-affinity sites organized as an exonic splicing enhancer activate splicing, linking sequence recognition to functional splice-site selection.","evidence":"SELEX, full-length binding assays, and in vitro splicing in S100 extracts","pmids":["7543047"],"confidence":"High","gaps":["Structural basis of the cooperative binding not resolved","Position-dependent enhancer/silencer effects not yet defined"]},{"year":1997,"claim":"Showed that SRSF1 activity is bidirectionally controlled by RS-domain phosphorylation, with phosphorylation needed for assembly and dephosphorylation required for the first catalytic transesterification, framing the protein as a phospho-switch in splicing.","evidence":"In vitro splicing with defined phospho-states and thiophosphorylation to block dephosphorylation","pmids":["9404896"],"confidence":"High","gaps":["Did not identify the responsible kinases and phosphatases","Did not connect phospho-state to subcellular localization"]},{"year":2000,"claim":"Identified SRPK1 as a direct physiological kinase for SRSF1, showing bacterially co-expressed phosphorylated SRSF1 is soluble and splicing-competent, establishing the upstream enzyme controlling the phospho-switch.","evidence":"Co-expression in E. coli with in vitro splicing and solubility assays","pmids":["10666475"],"confidence":"High","gaps":["Site specificity within the RS domain not mapped","Relationship to speckle localization not addressed"]},{"year":2005,"claim":"Resolved how sequential kinases partition SRSF1 between subnuclear compartments, showing SRPK1 phosphorylates the N-terminal RS region for speckle assembly and Clk/Sty the C-terminal region for release, mechanistically coupling phosphorylation to localization.","evidence":"SRPK1-SR peptide crystal structure, kinase assays with deletion mutants, and immunofluorescence localization","pmids":["16209947"],"confidence":"High","gaps":["Did not address the opposing phosphatase","In vivo consequences of mislocalization not tested"]},{"year":2007,"claim":"Defined the structural RNA-binding mode of RRM2 and revealed that the inter-RRM linker is a binding site for the export factor TAP that competes with RNA, providing the first molecular link between SRSF1 and mRNA export.","evidence":"NMR structure of RRM2 with RNA and TAP binding/competition assays","pmids":["17668007"],"confidence":"High","gaps":["Cellular export targets not yet identified","RRM1 recognition mode still undefined"]},{"year":2007,"claim":"Demonstrated that SRSF1 is an oncoprotein, showing overexpression transforms cells and forms tumors via splicing of BIN1, MNK2, and S6K1, converting a housekeeping splicing factor into a driver of malignancy.","evidence":"Transformation and xenograft assays with shRNA knockdown, RT-PCR splicing, and isoform-rescue epistasis","pmids":["17310252"],"confidence":"High","gaps":["Upstream signals controlling SRSF1 levels in cancer unknown","Full target spectrum not defined"]},{"year":2008,"claim":"Mapped the genome-wide SRSF1 binding landscape, showing thousands of purine-rich sites enriched near splice sites and over-represented on RNA-processing transcripts, scaling the binding logic to the transcriptome.","evidence":"CLIP-seq in HEK cells with motif analysis","pmids":["19116412"],"confidence":"Medium","gaps":["Did not establish positional rules for inclusion versus skipping","Functional consequence of most sites untested"]},{"year":2008,"claim":"Connected SRSF1 oncogenesis to a specific signaling output by showing it activates mTORC1 independently of Akt and that this is essential for transformation, linking splicing-factor function to translational control.","evidence":"Phospho-immunoblot, genetic knockdown of mTOR components, and rapamycin in focus-formation and xenograft assays","pmids":["18832178"],"confidence":"High","gaps":["Direct splicing/mRNA target driving mTORC1 not pinpointed","Mechanism of Akt bypass unresolved"]},{"year":2010,"claim":"Established that SRSF1 negatively autoregulates its own abundance through unproductive splicing coupled to NMD and RRM2/3'UTR-mediated translational repression, and that a miR-7 feedback loop reinforces this, defining how a potent oncoprotein is kept in check.","evidence":"Isoform analysis, polysome fractionation, mutagenesis, Dicer knockdown, RIP, Drosha cleavage and 3'UTR reporter assays","pmids":["20139984","20385090"],"confidence":"High","gaps":["How feedback is overridden in cancer not resolved here","miRNA-independent translational repression mechanism incompletely defined"]},{"year":2010,"claim":"Extended SRSF1 function beyond splicing by showing it stimulates global SUMO conjugation via Ubc9 and PIAS1 through its RRM2, identifying a moonlighting role in post-translational modification.","evidence":"Co-IP, knockdown/overexpression, in vitro and in vivo sumoylation, and domain mapping","pmids":["20805487"],"confidence":"High","gaps":["Catalytic basis of E3-like activity not structurally defined","Physiological SUMO substrate spectrum incomplete"]},{"year":2012,"claim":"Placed SRSF1 in the MYC oncogenic program from both directions, showing MYC transcriptionally activates SRSF1 and that SRSF1 cooperates with MYC to transform cells, establishing a feed-forward oncogenic circuit.","evidence":"ChIP, promoter reporters, MYC/SRSF1 knockdown, orthotopic transplantation, and 3D culture with MKNK2/TEAD1/BIN1/BIM splicing readouts","pmids":["22545246","22245967"],"confidence":"High","gaps":["Quantitative contribution of each splice target to transformation unclear","Tissue specificity of the circuit not mapped"]},{"year":2012,"claim":"Revealed a tumor-suppressive arm of SRSF1 by showing it is a necessary component of an RPL5-MDM2 complex that stabilizes p53 and triggers oncogene-induced senescence, explaining a fail-safe against SRSF1-driven transformation.","evidence":"Co-IP of the endogenous complex, p53 stability and senescence assays in primary fibroblasts","pmids":["23478443"],"confidence":"High","gaps":["Splicing-independence of this role not fully delineated","How cancers escape this senescence response unresolved"]},{"year":2015,"claim":"Resolved long-standing discrepancies by deriving positional rules from transcriptome-wide data, showing 5'-proximal SRSF1 binding favors inclusion while 3'-proximal binding can drive skipping or inclusion, and validated a downstream oncogenic isoform.","evidence":"RNA-seq in 3D culture, de novo motif discovery, Bayesian positional modeling, and CASC4 isoform overexpression","pmids":["26431027"],"confidence":"High","gaps":["Structural basis of position-dependent outcomes not addressed","Determinants of skip-versus-include at 3' sites unclear"]},{"year":2018,"claim":"Defined two additional post-transcriptional roles, showing SRSF1 stimulates UPF1-dependent NMD downstream of premature termination codons by recruiting UPF1 while bypassing UPF2, broadening its surveillance function.","evidence":"RIP, tethering and NMD reporter assays, and UPF2/EJC depletion","pmids":["29768215"],"confidence":"High","gaps":["Structural basis of UPF1 recruitment unknown","Relationship to EJC-dependent NMD not fully separated"]},{"year":2018,"claim":"Solved the structural basis for the opposing phosphatase, mapping the PP1 docking surface on RRM1 and showing its disruption lowers RS phosphorylation, redistributes SRSF1 from speckles, and shifts splicing, completing the kinase-phosphatase regulatory circuit.","evidence":"NMR, site-directed mutagenesis, in vitro dephosphorylation, FRAP, and RT-PCR splicing","pmids":["30185622"],"confidence":"High","gaps":["In vivo phenotype of PP1 uncoupling not tested","Crosstalk with SRPK/Clk timing unresolved"]},{"year":2020,"claim":"Showed that AMPK phosphorylates SRSF1 within the RRM at Ser133 to suppress RNA binding without altering localization, demonstrating that metabolic signaling can directly retune splice-site selection independently of the RS-domain switch.","evidence":"In vitro kinase assay, S133A mutagenesis, RNA-protein interaction and Ron splicing assays","pmids":["32453427"],"confidence":"High","gaps":["Genome-wide consequences of Ser133 phosphorylation untested","Physiological metabolic triggers in vivo not defined"]},{"year":2021,"claim":"Established that cytoplasmic shuttling of SRSF1 is physiologically required, showing nuclear-retained SRSF1 reduces translation of multiciliogenesis proteins and causes ciliary defects in mice, decoupling its cytoplasmic translational role from nuclear splicing.","evidence":"Nuclear-retention knock-in mouse with developmental phenotyping, polysome/translation assays, proteomics, and cilia EM","pmids":["34338635"],"confidence":"High","gaps":["Specific cytoplasmic mRNA targets driving ciliogenesis not enumerated","Mechanism of translational selectivity unclear"]},{"year":2021,"claim":"Demonstrated SRSF1 maintains genome integrity by suppressing R-loops, showing hepatocyte deletion causes RNA-DNA hybrid accumulation, DNA damage, and NASH-like pathology, linking its RNA processing role to genome protection in vivo.","evidence":"Hepatocyte-specific Srsf1 knockout mouse with S9.6 R-loop imaging, transcriptome/proteome sequencing, and eCLIP","pmids":["36759613"],"confidence":"High","gaps":["Direct biochemical mechanism of R-loop prevention not defined","Contribution of co-factors like RNPS1 not integrated"]},{"year":2021,"claim":"Defined a single-molecule, exon-independent recruitment of SRSF1 by U1 snRNP via contacts to U1 snRNA stem-loop 3, providing a mechanistic basis for U1-mediated exon definition beyond enhancer binding.","evidence":"Single-molecule fluorescence with structural cross-linking and stem-loop 3 mutagenesis","pmids":["34779515"],"confidence":"High","gaps":["Generality across endogenous exons not established","Interplay with enhancer-dependent recruitment unresolved"]},{"year":2019,"claim":"Established SRSF1 as a non-redundant controller of T-cell homeostasis and tolerance, showing T-cell Srsf1 deletion causes autoimmunity via a PTEN-mTORC1 axis rescuable by rapamycin or SRSF1 re-expression.","evidence":"T-cell conditional knockout mice with flow cytometry, PTEN/mTORC1 immunoblots, rapamycin, and overexpression rescue","pmids":["31487268","33863728","34233194","32206811"],"confidence":"High","gaps":["Direct splice/stability targets controlling PTEN not fully mapped","Cell-type-specific target sets across T-cell subsets incompletely defined"]},{"year":2023,"claim":"Linked SRSF1 dosage to human disease at both extremes, identifying haploinsufficiency as the cause of a syndromic neurodevelopmental disorder with a methylation episignature, while parallel work showed RNF125-mediated degradation and FANCD2-dependent export tie SRSF1 to oncogenic and genome-stability pathways.","evidence":"Drosophila in vivo splicing assays and methylation episignature in patients; Co-IP, ubiquitination, monoubiquitination, and mRNA export/R-loop assays","pmids":["37071997","37142680","38165804"],"confidence":"High","gaps":["Genotype-phenotype mechanism of the neurodevelopmental syndrome incompletely defined","Structural basis of the SRSF1-FANCD2 interaction unresolved"]},{"year":2023,"claim":"Identified PRMT1-mediated arginine methylation as an upstream determinant of SRSF1 phosphorylation, RNA binding, and exon inclusion, adding a methylation layer to the regulatory hierarchy with therapeutic implications in breast cancer.","evidence":"Methylome profiling, in vitro methylation, RNA binding, splicing assays, and pharmacological inhibition with iPRMT1 and SRPK inhibitors","pmids":["37938975"],"confidence":"High","gaps":["Methylated residues' structural impact not resolved","Hierarchy with phosphorylation timing not fully ordered"]},{"year":null,"claim":"How the multilayered modification code (SRPK/Clk phosphorylation, AMPK/Akt RRM phosphorylation, PRMT1 methylation, PP1 dephosphorylation) is integrated in real time to select specific splice, export, decay, and translation targets in a given cell state remains unresolved.","evidence":"No single study in the timeline integrates all modification inputs with target selection in vivo","pmids":[],"confidence":"Medium","gaps":["No unified model linking modification state to target choice","Cell-type-specific target rewiring not mechanistically explained","Structural basis of how modifications alter RRM/RS function incompletely defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,12,14,38,41]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,2,29,32]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[16,19,40]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[12,31,32,54]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[25,27]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[10,34]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10,25,46]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[16,40,46]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,2,16,17,29,32]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[25,27]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[12,31,45,54]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[13,22,35,51,52,53]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[36,42,47,48]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[39,49,54]}],"complexes":["nuclear speckles","RPL5-MDM2 complex","7SK snRNP","TREX/UAP56/ALYREF export complex"],"partners":["NXF1","SRPK1","PP1","UBC9","PIAS1","UPF1","FANCD2","RNF125"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q07955","full_name":"Serine/arginine-rich splicing factor 1","aliases":["Alternative-splicing factor 1","ASF-1","Splicing factor, arginine/serine-rich 1","pre-mRNA-splicing factor SF2, P33 subunit"],"length_aa":248,"mass_kda":27.7,"function":"Plays a role in preventing exon skipping, ensuring the accuracy of splicing and regulating alternative splicing. Interacts with other spliceosomal components, via the RS domains, to form a bridge between the 5'- and 3'-splice site binding components, U1 snRNP and U2AF. Can stimulate binding of U1 snRNP to a 5'-splice site-containing pre-mRNA. Binds to purine-rich RNA sequences, either the octamer, 5'-RGAAGAAC-3' (r=A or G) or the decamers, AGGACAGAGC/AGGACGAAGC. Binds preferentially to the 5'-CGAGGCG-3' motif in vitro. Three copies of the octamer constitute a powerful splicing enhancer in vitro, the ASF/SF2 splicing enhancer (ASE) which can specifically activate ASE-dependent splicing. Isoform ASF-2 and isoform ASF-3 act as splicing repressors. May function as export adapter involved in mRNA nuclear export through the TAP/NXF1 pathway","subcellular_location":"Cytoplasm; Nucleus speckle","url":"https://www.uniprot.org/uniprotkb/Q07955/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SRSF1","classification":"Common Essential","n_dependent_lines":1206,"n_total_lines":1208,"dependency_fraction":0.9983443708609272},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SNRPC","stoichiometry":10.0},{"gene":"CPSF6","stoichiometry":4.0},{"gene":"SNRPA","stoichiometry":4.0},{"gene":"SNRPB","stoichiometry":4.0},{"gene":"SNRPF","stoichiometry":4.0},{"gene":"ANKRD27","stoichiometry":0.2},{"gene":"ANKRD39","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"SCYL1","stoichiometry":0.2},{"gene":"SLC9A3R1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SRSF1","total_profiled":1310},"omim":[{"mim_id":"621181","title":"NF-KAPPA-B-INTERACTING LONG NONCODING RNA; NKILA","url":"https://www.omim.org/entry/621181"},{"mim_id":"620489","title":"NEURODEVELOPMENTAL DISORDER WITH DYSMORPHIC FACIES AND BEHAVIORAL ABNORMALITIES; NEDFBA","url":"https://www.omim.org/entry/620489"},{"mim_id":"617937","title":"RNA-BINDING MOTIF PROTEIN 11; RBM11","url":"https://www.omim.org/entry/617937"},{"mim_id":"617138","title":"SKI FAMILY TRANSCRIPTIONAL COREPRESSOR 2; SKOR2","url":"https://www.omim.org/entry/617138"},{"mim_id":"616173","title":"NUCLEAR SPECKLE SPLICING REGULATORY PROTEIN 1; NSRP1","url":"https://www.omim.org/entry/616173"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SRSF1"},"hgnc":{"alias_symbol":["ASF","SF2","SRp30a","SF2p33","MGC5228"],"prev_symbol":["SFRS1"]},"alphafold":{"accession":"Q07955","domains":[{"cath_id":"3.30.70.330","chopping":"13-86","consensus_level":"high","plddt":84.6319,"start":13,"end":86},{"cath_id":"3.30.70.330","chopping":"121-193","consensus_level":"high","plddt":93.0145,"start":121,"end":193}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q07955","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q07955-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q07955-F1-predicted_aligned_error_v6.png","plddt_mean":70.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRSF1","jax_strain_url":"https://www.jax.org/strain/search?query=SRSF1"},"sequence":{"accession":"Q07955","fasta_url":"https://rest.uniprot.org/uniprotkb/Q07955.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q07955/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q07955"}},"corpus_meta":[{"pmid":"20456941","id":"PMC_20456941","title":"SF1 and SF2 helicases: family matters.","date":"2010","source":"Current opinion in structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/20456941","citation_count":766,"is_preprint":false},{"pmid":"17310252","id":"PMC_17310252","title":"The gene encoding the splicing factor SF2/ASF is a proto-oncogene.","date":"2007","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17310252","citation_count":761,"is_preprint":false},{"pmid":"22245967","id":"PMC_22245967","title":"The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation.","date":"2012","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22245967","citation_count":364,"is_preprint":false},{"pmid":"2145194","id":"PMC_2145194","title":"Purification and characterization of pre-mRNA splicing factor SF2 from HeLa cells.","date":"1990","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/2145194","citation_count":327,"is_preprint":false},{"pmid":"16364913","id":"PMC_16364913","title":"Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene.","date":"2005","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/16364913","citation_count":320,"is_preprint":false},{"pmid":"7543047","id":"PMC_7543047","title":"The human splicing factors ASF/SF2 and SC35 possess distinct, functionally significant RNA binding specificities.","date":"1995","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/7543047","citation_count":317,"is_preprint":false},{"pmid":"26431027","id":"PMC_26431027","title":"SRSF1-Regulated Alternative Splicing in Breast Cancer.","date":"2015","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/26431027","citation_count":268,"is_preprint":false},{"pmid":"27993818","id":"PMC_27993818","title":"Long Noncoding RNA MALAT1 Promotes Hepatocellular Carcinoma Development by SRSF1 Upregulation and mTOR Activation.","date":"2016","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/27993818","citation_count":268,"is_preprint":false},{"pmid":"19116412","id":"PMC_19116412","title":"Splicing factor SFRS1 recognizes a functionally diverse landscape of RNA transcripts.","date":"2008","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/19116412","citation_count":256,"is_preprint":false},{"pmid":"24807918","id":"PMC_24807918","title":"Emerging functions of SRSF1, splicing factor and oncoprotein, in RNA metabolism and cancer.","date":"2014","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/24807918","citation_count":233,"is_preprint":false},{"pmid":"16209947","id":"PMC_16209947","title":"Interplay between SRPK and Clk/Sty kinases in phosphorylation of the splicing factor ASF/SF2 is regulated by a docking motif in ASF/SF2.","date":"2005","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/16209947","citation_count":178,"is_preprint":false},{"pmid":"27093186","id":"PMC_27093186","title":"Genomic Landscape Survey Identifies SRSF1 as a Key Oncodriver in Small Cell Lung Cancer.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27093186","citation_count":176,"is_preprint":false},{"pmid":"22545246","id":"PMC_22545246","title":"Oncogenic splicing factor SRSF1 is a critical transcriptional target of MYC.","date":"2012","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/22545246","citation_count":172,"is_preprint":false},{"pmid":"20139984","id":"PMC_20139984","title":"SF2/ASF autoregulation involves multiple layers of post-transcriptional and translational control.","date":"2010","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20139984","citation_count":164,"is_preprint":false},{"pmid":"9404896","id":"PMC_9404896","title":"Both phosphorylation and dephosphorylation of ASF/SF2 are required for pre-mRNA splicing in vitro.","date":"1997","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9404896","citation_count":164,"is_preprint":false},{"pmid":"20385090","id":"PMC_20385090","title":"A splicing-independent function of SF2/ASF in microRNA processing.","date":"2010","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/20385090","citation_count":160,"is_preprint":false},{"pmid":"24857172","id":"PMC_24857172","title":"MALAT1 promotes cell proliferation in gastric cancer by recruiting SF2/ASF.","date":"2014","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/24857172","citation_count":148,"is_preprint":false},{"pmid":"10022843","id":"PMC_10022843","title":"The splicing factor-associated protein, p32, regulates RNA splicing by inhibiting ASF/SF2 RNA binding and phosphorylation.","date":"1999","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/10022843","citation_count":144,"is_preprint":false},{"pmid":"30481162","id":"PMC_30481162","title":"Splicing factor SRSF1 promotes gliomagenesis via oncogenic splice-switching of MYO1B.","date":"2019","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/30481162","citation_count":123,"is_preprint":false},{"pmid":"21045158","id":"PMC_21045158","title":"Alternative splicing of caspase 9 is modulated by the phosphoinositide 3-kinase/Akt pathway via phosphorylation of SRp30a.","date":"2010","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/21045158","citation_count":113,"is_preprint":false},{"pmid":"22855529","id":"PMC_22855529","title":"SRSF1 regulates the assembly of pre-mRNA processing factors in nuclear speckles.","date":"2012","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/22855529","citation_count":110,"is_preprint":false},{"pmid":"28677678","id":"PMC_28677678","title":"SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28677678","citation_count":107,"is_preprint":false},{"pmid":"18832178","id":"PMC_18832178","title":"The splicing-factor oncoprotein SF2/ASF activates mTORC1.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18832178","citation_count":106,"is_preprint":false},{"pmid":"24468535","id":"PMC_24468535","title":"Mutual inhibition between YAP and SRSF1 maintains long non-coding RNA, Malat1-induced tumourigenesis in liver cancer.","date":"2014","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/24468535","citation_count":102,"is_preprint":false},{"pmid":"23592547","id":"PMC_23592547","title":"SRSF1 and SRSF9 RNA binding proteins promote Wnt signalling-mediated tumorigenesis by enhancing β-catenin biosynthesis.","date":"2013","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23592547","citation_count":101,"is_preprint":false},{"pmid":"33664238","id":"PMC_33664238","title":"SRSF1 inhibits autophagy through regulating Bcl-x splicing and interacting with PIK3C3 in lung cancer.","date":"2021","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33664238","citation_count":98,"is_preprint":false},{"pmid":"21118818","id":"PMC_21118818","title":"MicroRNAs-10a and -10b contribute to retinoic acid-induced differentiation of neuroblastoma cells and target the alternative splicing regulatory factor SFRS1 (SF2/ASF).","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21118818","citation_count":97,"is_preprint":false},{"pmid":"30429088","id":"PMC_30429088","title":"SRSF1 modulates PTPMT1 alternative splicing to regulate lung cancer cell radioresistance.","date":"2018","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/30429088","citation_count":93,"is_preprint":false},{"pmid":"23478443","id":"PMC_23478443","title":"Splicing-factor oncoprotein SRSF1 stabilizes p53 via RPL5 and induces cellular senescence.","date":"2013","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/23478443","citation_count":93,"is_preprint":false},{"pmid":"28799539","id":"PMC_28799539","title":"SRSF1 promotes vascular smooth muscle cell proliferation through a Δ133p53/EGR1/KLF5 pathway.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28799539","citation_count":84,"is_preprint":false},{"pmid":"23284704","id":"PMC_23284704","title":"Regulation of Mcl-1 by SRSF1 and SRSF5 in cancer cells.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23284704","citation_count":78,"is_preprint":false},{"pmid":"9611241","id":"PMC_9611241","title":"Interaction between the N-terminal domain of human DNA topoisomerase I and the arginine-serine domain of its substrate determines phosphorylation of SF2/ASF splicing factor.","date":"1998","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/9611241","citation_count":75,"is_preprint":false},{"pmid":"31487268","id":"PMC_31487268","title":"Splicing factor SRSF1 controls T cell hyperactivity and systemic autoimmunity.","date":"2019","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/31487268","citation_count":70,"is_preprint":false},{"pmid":"33602301","id":"PMC_33602301","title":"SRPK1/2 and PP1α exert opposite functions by modulating SRSF1-guided MKNK2 alternative splicing in colon adenocarcinoma.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/33602301","citation_count":70,"is_preprint":false},{"pmid":"17668007","id":"PMC_17668007","title":"Structural and functional analysis of RNA and TAP binding to SF2/ASF.","date":"2007","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/17668007","citation_count":66,"is_preprint":false},{"pmid":"16505493","id":"PMC_16505493","title":"SRp30a (ASF/SF2) regulates the alternative splicing of caspase-9 pre-mRNA and is required for ceramide-responsiveness.","date":"2006","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/16505493","citation_count":64,"is_preprint":false},{"pmid":"29262322","id":"PMC_29262322","title":"SRSF1 Prevents DNA Damage and Promotes Tumorigenesis through Regulation of DBF4B Pre-mRNA Splicing.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29262322","citation_count":63,"is_preprint":false},{"pmid":"29768215","id":"PMC_29768215","title":"Mechanism of Nonsense-Mediated mRNA Decay Stimulation by Splicing Factor SRSF1.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29768215","citation_count":61,"is_preprint":false},{"pmid":"16916529","id":"PMC_16916529","title":"Specific and distinct determinants mediate membrane binding and lipid raft incorporation of HIV-1(SF2) Nef.","date":"2006","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/16916529","citation_count":60,"is_preprint":false},{"pmid":"37098965","id":"PMC_37098965","title":"Splicing Factor SRSF1 Promotes Pancreatitis and KRASG12D-Mediated Pancreatic Cancer.","date":"2023","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37098965","citation_count":59,"is_preprint":false},{"pmid":"10092085","id":"PMC_10092085","title":"SF2 and SRp55 regulation of CD45 exon 4 skipping during T cell activation.","date":"1999","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10092085","citation_count":59,"is_preprint":false},{"pmid":"36199071","id":"PMC_36199071","title":"Circular RNA circPVT1 promotes nasopharyngeal carcinoma metastasis via the β-TrCP/c-Myc/SRSF1 positive feedback loop.","date":"2022","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36199071","citation_count":56,"is_preprint":false},{"pmid":"26887056","id":"PMC_26887056","title":"Long non-coding RNA MALAT1 increases AKAP-9 expression by promoting SRPK1-catalyzed SRSF1 phosphorylation in colorectal cancer cells.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26887056","citation_count":56,"is_preprint":false},{"pmid":"35405116","id":"PMC_35405116","title":"METTL3-stabilized lncRNA SNHG7 accelerates glycolysis in prostate cancer via SRSF1/c-Myc axis.","date":"2022","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/35405116","citation_count":54,"is_preprint":false},{"pmid":"34170441","id":"PMC_34170441","title":"Extracellular matrix stiffness controls VEGF165 secretion and neuroblastoma angiogenesis via the YAP/RUNX2/SRSF1 axis.","date":"2021","source":"Angiogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/34170441","citation_count":54,"is_preprint":false},{"pmid":"22839530","id":"PMC_22839530","title":"Correlation of SRSF1 and PRMT1 expression with clinical status of pediatric acute lymphoblastic leukemia.","date":"2012","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/22839530","citation_count":53,"is_preprint":false},{"pmid":"20805487","id":"PMC_20805487","title":"The serine/arginine-rich protein SF2/ASF regulates protein sumoylation.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20805487","citation_count":53,"is_preprint":false},{"pmid":"17959926","id":"PMC_17959926","title":"The RNA binding protein RNPS1 alleviates ASF/SF2 depletion-induced genomic instability.","date":"2007","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/17959926","citation_count":53,"is_preprint":false},{"pmid":"28657135","id":"PMC_28657135","title":"DNA-methylation-mediated repression of miR-766-3p promotes cell proliferation via targeting SF2 expression in renal cell carcinoma.","date":"2017","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28657135","citation_count":50,"is_preprint":false},{"pmid":"26273603","id":"PMC_26273603","title":"Posttranscriptional Regulation of Splicing Factor SRSF1 and Its Role in Cancer Cell Biology.","date":"2015","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/26273603","citation_count":48,"is_preprint":false},{"pmid":"20682707","id":"PMC_20682707","title":"The oncoprotein SF2/ASF promotes non-small cell lung cancer survival by enhancing survivin expression.","date":"2010","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/20682707","citation_count":47,"is_preprint":false},{"pmid":"33462199","id":"PMC_33462199","title":"Structure of SRSF1 RRM1 bound to RNA reveals an unexpected bimodal mode of interaction and explains its involvement in SMN1 exon7 splicing.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33462199","citation_count":47,"is_preprint":false},{"pmid":"31200124","id":"PMC_31200124","title":"The RNA-binding protein SRSF1 is a key cell cycle regulator via stabilizing NEAT1 in glioma.","date":"2019","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31200124","citation_count":46,"is_preprint":false},{"pmid":"25416801","id":"PMC_25416801","title":"HIV-1 transcription is regulated by splicing factor SRSF1.","date":"2014","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/25416801","citation_count":42,"is_preprint":false},{"pmid":"36759613","id":"PMC_36759613","title":"Splicing factor SRSF1 deficiency in the liver triggers NASH-like pathology and cell death.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36759613","citation_count":41,"is_preprint":false},{"pmid":"34099633","id":"PMC_34099633","title":"Long noncoding RNA DGCR5 involves in tumorigenesis of esophageal squamous cell carcinoma via SRSF1-mediated alternative splicing of Mcl-1.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34099633","citation_count":41,"is_preprint":false},{"pmid":"31655037","id":"PMC_31655037","title":"Long non-coding RNA MIR205HG regulates KRT17 and tumor processes in cervical cancer via interaction with SRSF1.","date":"2019","source":"Experimental and molecular pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31655037","citation_count":41,"is_preprint":false},{"pmid":"19464723","id":"PMC_19464723","title":"The hepatitis delta virus RNA genome interacts with eEF1A1, p54(nrb), hnRNP-L, GAPDH and ASF/SF2.","date":"2009","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/19464723","citation_count":40,"is_preprint":false},{"pmid":"30181552","id":"PMC_30181552","title":"The oncogenic RNA-binding protein SRSF1 regulates LIG1 in non-small cell lung cancer.","date":"2018","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/30181552","citation_count":37,"is_preprint":false},{"pmid":"34338635","id":"PMC_34338635","title":"Nucleo-cytoplasmic shuttling of splicing factor SRSF1 is required for development and cilia function.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34338635","citation_count":37,"is_preprint":false},{"pmid":"32819370","id":"PMC_32819370","title":"SRSF1 regulates exosome microRNA enrichment in human cancer cells.","date":"2020","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/32819370","citation_count":36,"is_preprint":false},{"pmid":"33863728","id":"PMC_33863728","title":"SRSF1 serves as a critical posttranscriptional regulator at the late stage of thymocyte development.","date":"2021","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/33863728","citation_count":36,"is_preprint":false},{"pmid":"32206811","id":"PMC_32206811","title":"Splicing factor SRSF1 controls T cell homeostasis and its decreased levels are linked to lymphopenia in systemic lupus erythematosus.","date":"2020","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/32206811","citation_count":34,"is_preprint":false},{"pmid":"34779515","id":"PMC_34779515","title":"Exon-independent recruitment of SRSF1 is mediated by U1 snRNP stem-loop 3.","date":"2021","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/34779515","citation_count":33,"is_preprint":false},{"pmid":"34233194","id":"PMC_34233194","title":"Splicing factor SRSF1 is indispensable for regulatory T cell homeostasis and function.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34233194","citation_count":32,"is_preprint":false},{"pmid":"37938975","id":"PMC_37938975","title":"Targeting PRMT1-mediated SRSF1 methylation to suppress oncogenic exon inclusion events and breast tumorigenesis.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37938975","citation_count":31,"is_preprint":false},{"pmid":"35163432","id":"PMC_35163432","title":"circSLC41A1 Resists Porcine Granulosa Cell Apoptosis and Follicular Atresia by Promoting SRSF1 through miR-9820-5p Sponging.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35163432","citation_count":31,"is_preprint":false},{"pmid":"21984412","id":"PMC_21984412","title":"Phosphorylation of SRSF1 is modulated by replicational stress.","date":"2011","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/21984412","citation_count":31,"is_preprint":false},{"pmid":"24890719","id":"PMC_24890719","title":"T cell activation regulates CD6 alternative splicing by transcription dynamics and SRSF1.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24890719","citation_count":30,"is_preprint":false},{"pmid":"38165804","id":"PMC_38165804","title":"The FANCI/FANCD2 complex links DNA damage response to R-loop regulation through SRSF1-mediated mRNA export.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38165804","citation_count":29,"is_preprint":false},{"pmid":"25641424","id":"PMC_25641424","title":"XPB: An unconventional SF2 DNA helicase.","date":"2015","source":"Progress in biophysics and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25641424","citation_count":28,"is_preprint":false},{"pmid":"31478261","id":"PMC_31478261","title":"SRSF1-dependent alternative splicing attenuates BIN1 expression in non-small cell lung cancer.","date":"2019","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31478261","citation_count":27,"is_preprint":false},{"pmid":"23161006","id":"PMC_23161006","title":"Structure and Mechanisms of SF2 DNA Helicases.","date":"2013","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/23161006","citation_count":27,"is_preprint":false},{"pmid":"38040194","id":"PMC_38040194","title":"SRSF1 inhibits ferroptosis and reduces cisplatin chemosensitivity of triple-negative breast cancer cells through the circSEPT9/GCH1 axis.","date":"2023","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/38040194","citation_count":27,"is_preprint":false},{"pmid":"32051529","id":"PMC_32051529","title":"SRSF1 mediates cytokine-induced impaired imatinib sensitivity in chronic myeloid leukemia.","date":"2020","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/32051529","citation_count":26,"is_preprint":false},{"pmid":"10666475","id":"PMC_10666475","title":"Functional coexpression of serine protein kinase SRPK1 and its substrate ASF/SF2 in Escherichia coli.","date":"2000","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/10666475","citation_count":26,"is_preprint":false},{"pmid":"22369183","id":"PMC_22369183","title":"Predicting sequence and structural specificities of RNA binding regions recognized by splicing factor SRSF1.","date":"2011","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/22369183","citation_count":26,"is_preprint":false},{"pmid":"34376242","id":"PMC_34376242","title":"SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis.","date":"2021","source":"Molecular neurodegeneration","url":"https://pubmed.ncbi.nlm.nih.gov/34376242","citation_count":25,"is_preprint":false},{"pmid":"34001131","id":"PMC_34001131","title":"CCL21 activation of the MALAT1/SRSF1/mTOR axis underpins the development of gastric carcinoma.","date":"2021","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34001131","citation_count":25,"is_preprint":false},{"pmid":"12270705","id":"PMC_12270705","title":"The RNA splicing factor ASF/SF2 inhibits human topoisomerase I mediated DNA relaxation.","date":"2002","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12270705","citation_count":24,"is_preprint":false},{"pmid":"34096602","id":"PMC_34096602","title":"Sequence-dependent recruitment of SRSF1 and SRSF7 to intronless lncRNA NKILA promotes nuclear export via the TREX/TAP pathway.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/34096602","citation_count":24,"is_preprint":false},{"pmid":"30185622","id":"PMC_30185622","title":"Molecular interactions connecting the function of the serine-arginine-rich protein SRSF1 to protein phosphatase 1.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30185622","citation_count":24,"is_preprint":false},{"pmid":"32810232","id":"PMC_32810232","title":"Splicing factor SRSF1 limits IFN-γ production via RhoH and ameliorates experimental nephritis.","date":"2021","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/32810232","citation_count":23,"is_preprint":false},{"pmid":"35442145","id":"PMC_35442145","title":"LINC00857 regulated by ZNF460 enhances the expression of CLDN12 by sponging miR-150-5p and recruiting SRSF1 for alternative splicing to promote epithelial-mesenchymal transformation of pancreatic adenocarcinoma cells.","date":"2021","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/35442145","citation_count":23,"is_preprint":false},{"pmid":"37973660","id":"PMC_37973660","title":"Targeting alternative splicing as a new cancer immunotherapy-phosphorylation of serine arginine-rich splicing factor (SRSF1) by SR protein kinase 1 (SRPK1) regulates alternative splicing of PD1 to generate a soluble antagonistic isoform that prevents T cell exhaustion.","date":"2023","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/37973660","citation_count":22,"is_preprint":false},{"pmid":"34195277","id":"PMC_34195277","title":"lncRNA LINC01296 Promotes Oral Squamous Cell Carcinoma Development by Binding with SRSF1.","date":"2021","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/34195277","citation_count":22,"is_preprint":false},{"pmid":"35027535","id":"PMC_35027535","title":"USP15 and USP4 facilitate lung cancer cell proliferation by regulating the alternative splicing of SRSF1.","date":"2022","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/35027535","citation_count":21,"is_preprint":false},{"pmid":"32888503","id":"PMC_32888503","title":"Splicing Factor SRSF1 Is Essential for Satellite Cell Proliferation and Postnatal Maturation of Neuromuscular Junctions in Mice.","date":"2020","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32888503","citation_count":21,"is_preprint":false},{"pmid":"34453920","id":"PMC_34453920","title":"Propofol suppresses colorectal cancer development by the circ-PABPN1/miR-638/SRSF1 axis.","date":"2021","source":"Analytical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34453920","citation_count":21,"is_preprint":false},{"pmid":"37071997","id":"PMC_37071997","title":"SRSF1 haploinsufficiency is responsible for a syndromic developmental disorder associated with intellectual disability.","date":"2023","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37071997","citation_count":20,"is_preprint":false},{"pmid":"32453427","id":"PMC_32453427","title":"AMP-activated protein kinase regulates alternative pre-mRNA splicing by phosphorylation of SRSF1.","date":"2020","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/32453427","citation_count":20,"is_preprint":false},{"pmid":"23966470","id":"PMC_23966470","title":"Tissue-specific and SRSF1-dependent splicing of fibronectin, a matrix protein that controls host cell invasion.","date":"2013","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/23966470","citation_count":20,"is_preprint":false},{"pmid":"27363031","id":"PMC_27363031","title":"Antibody neutralization of cell-surface gC1qR/HABP1/SF2-p32 prevents lamellipodia formation and tumorigenesis.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27363031","citation_count":19,"is_preprint":false},{"pmid":"12135490","id":"PMC_12135490","title":"SF2/ASF protein inhibits camptothecin-induced DNA cleavage by human topoisomerase I.","date":"2002","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12135490","citation_count":19,"is_preprint":false},{"pmid":"37142680","id":"PMC_37142680","title":"RNF125 attenuates hepatocellular carcinoma progression by downregulating SRSF1-ERK pathway.","date":"2023","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/37142680","citation_count":18,"is_preprint":false},{"pmid":"36882745","id":"PMC_36882745","title":"SRSF1 regulates primordial follicle formation and number determination during meiotic prophase I.","date":"2023","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/36882745","citation_count":17,"is_preprint":false},{"pmid":"37781512","id":"PMC_37781512","title":"SRSF1-mediated alternative splicing is required for spermatogenesis.","date":"2023","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37781512","citation_count":17,"is_preprint":false},{"pmid":"34723963","id":"PMC_34723963","title":"A behavioral screen for mediators of age-dependent TDP-43 neurodegeneration identifies SF2/SRSF1 among a group of potent suppressors in both neurons and glia.","date":"2021","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34723963","citation_count":17,"is_preprint":false},{"pmid":"26456193","id":"PMC_26456193","title":"Genome-wide identification of SF1 and SF2 helicases from archaea.","date":"2015","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/26456193","citation_count":17,"is_preprint":false},{"pmid":"33670012","id":"PMC_33670012","title":"BAF57/SMARCE1 Interacting with Splicing Factor SRSF1 Regulates Mechanical Stress-Induced Alternative Splicing of Cyclin D1.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/33670012","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48323,"output_tokens":14072,"usd":0.178025,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":26077,"output_tokens":7603,"usd":0.16023,"stage2_stop_reason":"end_turn"},"total_usd":0.338255,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"SF2/ASF (SRSF1) was purified to near homogeneity from HeLa cells as a ~33 kDa protein necessary for 5' splice site cleavage and lariat formation during pre-mRNA splicing in vitro. It is sufficient to complement an S100 fraction for splicing and appears required for assembly or stabilization of the earliest prespliceosome complex. The purified protein also carries RNA annealing activity.\",\n      \"method\": \"Protein purification to near homogeneity; in vitro splicing complementation assay; RNA annealing assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro splicing activity with near-homogeneous protein, multiple functional assays\",\n      \"pmids\": [\"2145194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"SELEX experiments with the RNA-binding domains of ASF/SF2 (SRSF1) and SC35 showed they recognize distinct purine-rich RNA motifs. Full-length protein binding assays confirmed the specificities are distinct and that the charged RS region is not a major specificity determinant for ASF/SF2. Cooperation between the two RBDs of ASF/SF2 determines binding specificity. An exonic splicing enhancer (ESE) containing three copies of a high-affinity ASF/SF2 binding site potently activates splicing in a manner that requires ASF/SF2 plus additional factors in S100 extracts.\",\n      \"method\": \"SELEX (in vitro RNA selection); RNA binding assays with full-length proteins; in vitro splicing assay in S100 extracts\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — SELEX plus binding assays plus functional splicing reconstitution, multiple orthogonal methods\",\n      \"pmids\": [\"7543047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Both phosphorylation and dephosphorylation of ASF/SF2 (SRSF1) are required for pre-mRNA splicing in vitro. Phosphorylated ASF/SF2 complements SR-protein-deficient S100 extracts; unphosphorylated protein inhibits splicing. Thiophosphorylated (non-dephosphorylatable) ASF/SF2 supports spliceosome assembly but blocks the first transesterification reaction, demonstrating that dephosphorylation is required for the catalytic step.\",\n      \"method\": \"In vitro splicing assay; phosphorylation/dephosphorylation of recombinant ASF/SF2; thiophosphorylation to block dephosphorylation\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro splicing with biochemically defined phosphorylation states, multiple conditions tested\",\n      \"pmids\": [\"9404896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human DNA topoisomerase I (topo I) phosphorylates SF2/ASF (SRSF1) exclusively within the extended arginine-serine repeats of the RS domain. The N-terminal 174 amino acids of topo I are required for binding SF2/ASF; deletion of this region abolishes both binding and kinase activity. Kinase activity and SF2/ASF binding are tightly coupled; the C-terminal region of topo I contains the ATP-binding site.\",\n      \"method\": \"In vitro kinase assay; far-western blotting; fluorescence spectroscopy; deletion mutagenesis of topo I and SF2/ASF\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase reconstitution with mutagenesis and multiple binding assays, single lab\",\n      \"pmids\": [\"9611241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The cellular protein p32 was co-purified with ASF/SF2 (SRSF1) and shown to interact directly with ASF/SF2 and SRp30c. p32 inhibits ASF/SF2 function as a splicing enhancer and splicing repressor by preventing stable RNA binding. p32 also inhibits phosphorylation of ASF/SF2 by HeLa nuclear extracts and specific SR kinases, placing p32 as a negative regulator that sequesters ASF/SF2 into an inhibitory complex.\",\n      \"method\": \"Co-purification; in vitro splicing assay; RNA binding assay; in vitro kinase assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple biochemical assays (co-purification, splicing, RNA binding, kinase), single lab\",\n      \"pmids\": [\"10022843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SF2/ASF (SRSF1) controls alternative splicing of CD45 exon 4; its RRM domains (not the RS domain) are required for this skipping activity. Overexpression of SF2 induces CD45 exon 4 skipping in COS cells. SF2 is upregulated during T cell activation, coinciding with a shift from CD45RA to CD45RO isoform expression.\",\n      \"method\": \"Overexpression in COS cells; deletion mutant analysis; T cell activation assays; flow cytometry\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — overexpression with domain mutants and cellular readout, single lab\",\n      \"pmids\": [\"10092085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SRPK1 co-expressed with ASF/SF2 in E. coli phosphorylates ASF/SF2 to a degree resembling native HeLa cell ASF/SF2. The E. coli-phosphorylated ASF/SF2 is functional in splicing and, unlike unphosphorylated protein, is soluble under native conditions, demonstrating that SRPK1 is a direct kinase for SRSF1.\",\n      \"method\": \"Co-expression in E. coli; in vitro splicing assay; protein solubility assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted phosphorylation and functional splicing in bacteria, clear biochemical readout\",\n      \"pmids\": [\"10666475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"ASF/SF2 (SRSF1) inhibits DNA relaxation by human topoisomerase I by interfering with the DNA cleavage and/or DNA binding steps of topoisomerase I catalysis. Inhibition correlates with direct interaction between the RS domain of ASF/SF2 and residues 208–735 of topoisomerase I. Phosphorylation of the RS domain reduces this inhibition.\",\n      \"method\": \"In vitro topoisomerase I relaxation assay; deletion mutant interaction mapping; phosphorylation experiments\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro biochemical assay with mutagenesis, single lab\",\n      \"pmids\": [\"12270705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SF2/ASF (SRSF1) inhibits camptothecin-induced DNA cleavage by human topoisomerase I by reducing formation of the cleavable complex; this inhibition is independent of the phosphorylation status of SF2/ASF and does not result from SF2/ASF binding to DNA.\",\n      \"method\": \"In vitro topoisomerase I cleavage assay; camptothecin treatment; phosphorylation controls\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical assay, single lab, single method\",\n      \"pmids\": [\"12135490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SF2/ASF (SRSF1) directly binds a splicing enhancer in exon 12 of the Ron tyrosine kinase receptor pre-mRNA and controls skipping of exon 11 to generate constitutively active DeltaRon. Overexpression and RNAi of SF2/ASF demonstrate it directly controls epithelial-to-mesenchymal transition and cell motility through DeltaRon isoform production. Knockdown of DeltaRon mRNA reverses the motility effect of SF2/ASF overexpression.\",\n      \"method\": \"RNA binding assay; overexpression and RNAi; RT-PCR splicing assay; cell motility assay; epistasis by DeltaRon knockdown\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated, RNAi epistasis rescue experiment, multiple orthogonal methods\",\n      \"pmids\": [\"16364913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure of SRPK1 bound to an SR-protein peptide identified a docking motif in ASF/SF2 (SRSF1). This docking motif restricts SRPK1-mediated phosphorylation to the N-terminal portion of the RS domain, which is essential for assembly of ASF/SF2 into nuclear speckles. Clk/Sty kinase subsequently phosphorylates the C-terminal portion of the RS domain, causing release of ASF/SF2 from speckles. Sequential phosphorylation by SRPK1 then Clk/Sty thus controls subcellular localization.\",\n      \"method\": \"Crystal structure; in vitro kinase assay with deletion mutants; subcellular localization by immunofluorescence; docking motif mutagenesis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and functional localization assay, multiple orthogonal methods\",\n      \"pmids\": [\"16209947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SRp30a (SRSF1) regulates the alternative splicing of caspase-9 pre-mRNA: its downregulation by RNAi increases the antiapoptotic caspase-9b isoform and decreases the proapoptotic caspase-9a isoform. SRp30a is also required for ceramide to induce inclusion of the exon 3/4/5/6 cassette of caspase-9.\",\n      \"method\": \"RNAi knockdown; RT-PCR splicing assay; ceramide treatment\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with specific splicing readout and signal pathway perturbation, single lab\",\n      \"pmids\": [\"16505493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NMR structure of RRM2 of SF2/ASF (SRSF1) revealed that RRM2 binds RNA using a conserved SWQLKD tryptophan on helix α1 combined with strand β2 residues and a histidine on loop 5 — a novel RNA-binding mode. The linker connecting RRM1 and RRM2 contains arginine residues that form a binding site for the mRNA export factor TAP; TAP binding to this linker displaces RNA bound to RRM2.\",\n      \"method\": \"NMR structure determination; RNA binding assay; TAP binding assay with competition experiment\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure plus functional binding validation, single lab but two orthogonal approaches\",\n      \"pmids\": [\"17668007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SF2/ASF (SRSF1) overexpression transforms immortal rodent fibroblasts that form sarcomas in nude mice; transformation is driven in part by alternative splicing of BIN1 (generating isoforms lacking tumor-suppressor activity), MNK2 (producing an isoform with MAP kinase-independent eIF4E phosphorylation), and S6K1 (producing an oncogenic isoform). Knockdown of SF2/ASF or the oncogenic S6K1 isoform reverses transformation in vitro and in vivo.\",\n      \"method\": \"Overexpression transformation assay; nude mouse xenograft; shRNA knockdown; RT-PCR splicing; epistasis by S6K1 isoform knockdown\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo transformation with multiple splice-target validations and rescue experiments, replicated across targets\",\n      \"pmids\": [\"17310252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CLIP-seq of SFRS1 (SRSF1) in human embryonic kidney cells identified 23,632 binding sites across diverse RNA classes (mRNA, miRNA, snoRNA, ncRNA) sharing a purine-rich consensus motif. SFRS1-bound sequences are enriched near splice sites. mRNAs encoding RNA processing factors are significantly over-represented among SFRS1 targets.\",\n      \"method\": \"CLIP-seq (cross-linking immunoprecipitation and high-throughput sequencing); motif analysis\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide CLIP-seq with motif validation, single lab\",\n      \"pmids\": [\"19116412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SF2/ASF (SRSF1) overexpression activates the mTORC1 branch of the mTOR pathway, measured by S6K and 4EBP1 phosphorylation, without activating Akt (mTORC2 substrate). mTORC1 activation bypasses upstream PI3K/Akt signaling and is essential for SF2/ASF-mediated transformation; rapamycin blocks transformation in vitro and in vivo.\",\n      \"method\": \"Phosphorylation immunoblot; shRNA knockdown of mTOR, Raptor, Rictor; rapamycin inhibition; focus formation and xenograft assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic and pharmacological perturbations with specific pathway readouts, in vitro and in vivo\",\n      \"pmids\": [\"18832178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SF2/ASF (SRSF1) negatively autoregulates its own expression through multiple post-transcriptional and translational mechanisms. Unproductive alternative splicing (generating NMD-sensitive isoforms) accounts for part of the autoregulation. The primary mechanism is translational repression mediated by RRM2 and the ultraconserved 3'UTR. Overexpression shifts the target mRNA toward monoribosomes. Translational repression is partly independent of Dicer and 5' cap.\",\n      \"method\": \"RT-PCR isoform analysis; polysome fractionation; mutagenesis of RRM2 and 3'UTR; Dicer knockdown\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (isoform analysis, polysome profiling, mutagenesis), single lab\",\n      \"pmids\": [\"20139984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SF2/ASF (SRSF1) directly interacts with the primary miR-7 transcript (pri-miR-7) to facilitate Drosha cleavage, promoting miR-7 maturation independently of its splicing function. Mature miR-7 in turn targets the 3'UTR of SF2/ASF to repress its translation, forming a negative feedback loop. Similar regulation may apply to miR-221 and miR-222.\",\n      \"method\": \"miRNA deep sequencing; RNA immunoprecipitation; Drosha cleavage assay; 3'UTR reporter assay; overexpression and knockdown\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP, functional Drosha assay, reporter assay — multiple orthogonal methods, single lab\",\n      \"pmids\": [\"20385090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SF2/ASF (SRSF1) is a regulator of the SUMO conjugation pathway: overexpression stimulates and knockdown inhibits global SUMO conjugation. SRSF1 interacts with the SUMO E2 enzyme Ubc9 and the E3 ligase PIAS1, and RRM2 is necessary and sufficient for sumoylation enhancement. SRSF1 promotes sumoylation of RNA processing factors and is involved in heat-shock-induced sumoylation.\",\n      \"method\": \"Co-immunoprecipitation; overexpression and knockdown; in vitro and in vivo sumoylation assay; domain deletion analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vivo and in vitro sumoylation, domain mapping — multiple orthogonal methods, single lab\",\n      \"pmids\": [\"20805487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SRSF1 overexpression in NSCLC cells promotes survival by binding survivin mRNA, enhancing its translation through an mTORC1/4E-BP1-dependent mechanism, and increasing survivin mRNA stability. SRSF1 knockdown reduces survivin protein and induces apoptosis.\",\n      \"method\": \"RNA immunoprecipitation; mTORC1 inhibition (rapamycin); siRNA knockdown; western blot; mRNA stability assay\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and functional pharmacological inhibition, single lab, two orthogonal methods\",\n      \"pmids\": [\"20682707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Akt phosphorylates SRSF1 (SRp30a) at serines 199, 201, 227, and 234 via the PI3K/Akt pathway, mediating exclusion of the exon 3/4/5/6 cassette of caspase-9 pre-mRNA to produce antiapoptotic caspase-9b in NSCLC cells.\",\n      \"method\": \"PI3K/Akt inhibition; phosphorylation mapping by site-directed mutagenesis; RT-PCR splicing assay; EGFR overexpression/mutation models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation site mutagenesis with functional splicing readout, pathway inhibition, single lab\",\n      \"pmids\": [\"21045158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SRSF1 is hyperphosphorylated in response to chronic replication-dependent DNA damage (ATM activation) in 46BR.1G1 cells; this hyperphosphorylation is partially prevented by ATM inhibitor caffeine. Hyperphosphorylation of SRSF1 alters its subnuclear distribution and shifts the alternative splicing of target genes.\",\n      \"method\": \"Proteomic phosphorylation analysis; ATM inhibition; immunofluorescence subnuclear localization; RT-PCR splicing assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus localization and functional splicing readout, single lab\",\n      \"pmids\": [\"21984412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SRSF1 overexpression in mammary epithelial cells promotes alternative splicing of BIM and BIN1 to generate isoforms lacking pro-apoptotic functions, contributing to increased proliferation and delayed apoptosis. These oncogenic effects require RRM1 and nuclear functions of SRSF1. SRSF1 cooperates specifically with MYC to transform mammary epithelial cells, in part by potentiating eIF4E activation.\",\n      \"method\": \"Overexpression in MCF-10A and COMMA-1D cells; orthotopic transplantation; 3D culture; RT-PCR splicing; domain deletion analysis; MYC co-expression\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo orthotopic tumor model, 3D culture, domain mutagenesis, epistasis with MYC — multiple orthogonal methods, replicated\",\n      \"pmids\": [\"22245967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MYC directly activates transcription of SRSF1 through two non-canonical E-boxes in its promoter. Increased SRSF1 downstream of MYC is sufficient to modulate alternative splicing of MKNK2 and TEAD1. SRSF1 knockdown reduces MYC oncogenic activity (proliferation, anchorage-independent growth).\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP); promoter reporter assay; MYC knockdown; SRSF1 knockdown; RT-PCR splicing assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, promoter reporter, and functional KD with splicing readout — multiple orthogonal methods, single lab\",\n      \"pmids\": [\"22545246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SRSF1 is a necessary component of an MDM2/RPL5 ribosomal protein complex (separate from the ribosome) that stabilizes p53 by abrogating MDM2-dependent proteasomal degradation. Increased SRSF1 expression in primary human fibroblasts induces p53-dependent oncogene-induced senescence (OIS), implicating RPL5-MDM2 complex in OIS.\",\n      \"method\": \"Co-immunoprecipitation; p53 stability assay; SRSF1 overexpression in primary fibroblasts; senescence assays (SA-β-gal); MDM2 inhibition controls\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of endogenous complex, functional OIS readout, pathway epistasis — multiple orthogonal methods, single lab\",\n      \"pmids\": [\"23478443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SRSF1 depletion in human cells compromises association of splicing factors with nuclear speckles and influences levels/activity of other SR proteins. SRSF1, together with lncRNA MALAT1, can nucleate assembly of nuclear speckles. On a stably integrated reporter gene locus, SRSF1 promotes RNA Pol II-mediated transcription.\",\n      \"method\": \"siRNA knockdown; immunofluorescence of nuclear speckle markers; reporter gene assay with stable integration; FRAP-like analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with localization readout and reporter gene assay, single lab\",\n      \"pmids\": [\"22855529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SRSF1 directly controls alternative splicing of fibronectin EDA exon inclusion in human primary endometrial fibroblasts; RNAi knockdown of SRSF1 reduces EDA+ fibronectin, and higher SRSF1 expression in endometrium is linked to stronger EDA exon inclusion and consequently greater trophoblast invasion capacity in co-culture assay.\",\n      \"method\": \"RNAi; RT-PCR splicing assay; co-culture invasion assay; quantitative protein expression analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with splicing readout and functional invasion assay, single lab\",\n      \"pmids\": [\"23966470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HIV-1 transcription factor SRSF1 and Tat recognize overlapping sequences within TAR RNA and 7SK RNA. SRSF1 can increase basal HIV-1 transcription in the absence of Tat by recruiting P-TEFb to TAR from the 7SK snRNP, and can inhibit Tat transactivation by directly competing for TAR binding.\",\n      \"method\": \"RNA binding competition assay; Tat transactivation reporter assay; co-immunoprecipitation with 7SK snRNP components; overexpression/knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding competition and transcription reporter, single lab\",\n      \"pmids\": [\"25416801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SRSF1 binds to CD6 intron 4 and activates exon 5 splicing (promoting exon 5 inclusion). During T cell activation, SRSF1 levels decrease, its recruitment to the CD6 transcript is impaired by increased chromatin acetylation, and this leads to exon 5 skipping generating CD6Δd3, which no longer localizes at the immunological synapse.\",\n      \"method\": \"RNA immunoprecipitation; chromatin immunoprecipitation; HDAC inhibitor treatment; overexpression/knockdown; RT-PCR\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and ChIP with functional localization readout, single lab\",\n      \"pmids\": [\"24890719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RNA-seq in 3D MCF-10A cultures identified hundreds of SRSF1-regulated alternative splicing events. De novo motif discovery reconciled previous discrepancies. Bayesian positional modeling showed that SRSF1 binding near the 5' splice site generally promotes exon inclusion, whereas binding near the 3' splice site promotes either skipping or inclusion. Overexpression of an SRSF1-regulated exon-9-included CASC4 isoform partially recapitulates SRSF1's oncogenic effects.\",\n      \"method\": \"RNA-seq; de novo motif discovery; Bayesian positional model; RT-PCR validation; CASC4 isoform overexpression in 3D culture\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide RNA-seq with computational modeling and functional validation of a downstream target, multiple orthogonal methods\",\n      \"pmids\": [\"26431027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SRSF1 promotes vascular smooth muscle cell (VSMC) proliferation by favoring production of the truncated p53 isoform Δ133p53. Δ133p53 transcriptionally activates KLF5 via a Δ133p53-EGR1 complex, accelerating cell-cycle progression. SMC-specific Srsf1 knockout mice develop less intimal thickening after wire injury, and Srsf1 overexpression in rat arteries enhances neointima formation.\",\n      \"method\": \"Conditional SMC-specific knockout mouse; wire injury model; adenoviral overexpression; immunoprecipitation of Δ133p53-EGR1 complex; siRNA knockdown; cell proliferation assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO and overexpression with mechanistic complex IP, multiple orthogonal methods\",\n      \"pmids\": [\"28799539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Depletion of SRSF1 specifically prevents nuclear export of pathological C9ORF72 repeat-containing transcripts via the NXF1 pathway, suppressing dipeptide repeat protein production and neurodegeneration in Drosophila and patient-derived neurons. Preventing the interaction of SRSF1 with NXF1 also inhibits this export and alleviates neurotoxicity.\",\n      \"method\": \"SRSF1 depletion in Drosophila (genetic); patient-derived motor neuron co-culture; SRSF1-NXF1 interaction disruption; nuclear/cytoplasmic fractionation; repeat RNA export assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo Drosophila model, patient-derived neurons, mechanistic interaction disruption — replicated across systems\",\n      \"pmids\": [\"28677678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SRSF1 stimulates nonsense-mediated mRNA decay (NMD) by increasing UPF1 binding to mRNAs while in or associated with the nucleus, bypassing UPF2 recruitment. SRSF1 acts downstream of a PTC in a manner analogous to the EJC, and splicing/EJC deposition enhances the SRSF1-mediated NMD effect.\",\n      \"method\": \"RNA immunoprecipitation; tethering assay; NMD reporter assay; UPF2 depletion; EJC depletion; endogenous PTC-containing transcript analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP, reporter tethering, and multiple depletion experiments, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29768215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SRSF1 binds to LIG1 mRNA and regulates LIG1 expression by increasing mRNA stability and enhancing translation in an mTOR-dependent manner in NSCLC cells.\",\n      \"method\": \"RNA immunoprecipitation; mRNA stability assay; mTOR inhibition (rapamycin); siRNA knockdown; western blot\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and functional mRNA stability/translation assays, single lab\",\n      \"pmids\": [\"30181552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NMR spectroscopy identified two electrostatic residues in helix α2 and a hydrophobic residue in helix α1 of RRM1 of SRSF1 as the binding surface for protein phosphatase 1 (PP1). Mutations in these residues dissociate SRSF1 from PP1, enhance phosphatase activity, reduce RS domain phosphorylation, shift alternative splicing patterns, and increase SRSF1 diffusion from speckles to the nucleoplasm.\",\n      \"method\": \"NMR spectroscopy; site-directed mutagenesis; in vitro dephosphorylation assay; FRAP (diffusion from speckles); RT-PCR splicing assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with mutagenesis, functional phosphatase assay, and localization/splicing readouts — multiple orthogonal methods\",\n      \"pmids\": [\"30185622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SRSF1 controls alternative splicing of MYO1B to produce membrane-localized oncogenic MYO1B-fl isoform in glioma. SRSF1-guided AS of MYO1B activates PDK1/AKT and PAK/LIMK pathways to promote cell proliferation, survival, and invasion.\",\n      \"method\": \"RNA-seq; RT-PCR splicing assay; siRNA knockdown; MYO1B-fl overexpression; pathway inhibition; xenograft model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq, splicing validation, pathway epistasis, in vivo model — multiple orthogonal methods, single lab\",\n      \"pmids\": [\"30481162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"T cell-restricted Srsf1-deficient mice develop systemic autoimmunity; T cells show reduced PTEN expression and increased mTORC1 activity. mTORC1 inhibitor rapamycin suppresses proinflammatory cytokine production and autoimmunity in Srsf1-deficient mice. SRSF1 overexpression restores PTEN and suppresses mTORC1 activation, establishing an SRSF1–PTEN–mTORC1 axis in T cells.\",\n      \"method\": \"T cell-conditional Srsf1 knockout mouse; flow cytometry; immunoblot of PTEN and mTORC1 targets; rapamycin treatment; SRSF1 overexpression rescue\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse with mechanistic pathway rescue, pharmacological epistasis, replicated in patient samples\",\n      \"pmids\": [\"31487268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AMP-activated protein kinase (AMPK) directly phosphorylates SRSF1 at Ser133 within RRM. Ser133 phosphorylation suppresses SRSF1 interaction with specific RNA sequences without altering subcellular localization, and AMPK-dependent phosphorylation of SRSF1 regulates alternative splicing of Ron pre-mRNA by suppressing SRSF1 binding to exon 12.\",\n      \"method\": \"In vitro kinase assay; site-directed mutagenesis (S133A); RNA-protein interaction assay; RT-PCR splicing assay; subcellular fractionation\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase reconstitution with phosphosite mutagenesis and functional RNA-binding/splicing readouts, single lab\",\n      \"pmids\": [\"32453427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NMR and structural analysis of SRSF1 RRM1 revealed that it binds preferentially to a CN motif (C followed by any nucleotide). The flexible inter-RRM linker allows RRM1 to bind RNA on both sides of the RRM2 binding site (bimodal interaction mode). An E87N mutation in RRM1 engineered from this structure enables binding to uridines and activates SMN exon 7 inclusion.\",\n      \"method\": \"NMR structure determination; RNA binding assay; site-directed mutagenesis (E87N); splicing assay (SMN exon 7 inclusion)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with mutagenesis and functional splicing validation, structure-function relationship established\",\n      \"pmids\": [\"33462199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRSF1 depletion prevents R-loop formation in hepatocytes; SRSF1 loss causes excessive RNA-DNA hybrids, induces DNA damage, globally inhibits mRNA transcription and protein synthesis, impairs lipid metabolism/trafficking, and leads to necroptotic cell death with NASH-like liver pathology in mice. These effects are reproduced in SRSF1-depleted human liver cancer cells.\",\n      \"method\": \"Hepatocyte-specific conditional Srsf1 knockout mouse; R-loop immunofluorescence (S9.6 antibody); transcriptome and proteome sequencing; RNA binding analysis (eCLIP); liver pathology\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse with transcriptome/proteome/CLIP multi-omics, in vivo and human cell validation\",\n      \"pmids\": [\"36759613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRSF1 nuclear retention (via knock-in NRS) in mice causes small body size, hydrocephalus, and immotile sperm due to ciliary defects. Nuclear-retained SRSF1 reduces translation of a subset of mRNAs and decreases abundance of proteins involved in multiciliogenesis, disrupting ciliary ultrastructure and motility, demonstrating that cytoplasmic shuttling of SRSF1 is required for ciliogenesis.\",\n      \"method\": \"Genome editing (knock-in NRS); mouse developmental phenotyping; polysome/translation assay; proteomics; electron microscopy of cilia\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knock-in mouse model with multiple orthogonal readouts (proteomics, translation, electron microscopy), direct mechanistic link to shuttling\",\n      \"pmids\": [\"34338635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A single molecule of SRSF1 can be recruited by a U1 snRNP independently of exon sequences. Structural and cross-linking data show SRSF1 contacts U1 snRNA stem-loop 3. This exon-independent recruitment is proposed to underlie exon definition by U1 snRNP.\",\n      \"method\": \"Single-molecule fluorescence; structural NMR/cross-linking analysis; mutagenesis of stem-loop 3\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — single-molecule methods combined with structural cross-linking and mutagenesis, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"34779515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRSF1 conditional deletion in T cells causes T cell lymphopenia with increased apoptosis and decreased expression of anti-apoptotic Bcl-xL. SRSF1 overexpression rescues T cell survival from SLE patients, establishing a direct role for SRSF1 in controlling Bcl-xL expression and T cell homeostasis.\",\n      \"method\": \"Conditional Srsf1 KO mouse; flow cytometry (apoptosis); quantitative PCR and immunoblot of Bcl-xL; SRSF1 overexpression rescue in human T cells\",\n      \"journal\": \"Rheumatology (Oxford, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with mechanistic rescue, single lab\",\n      \"pmids\": [\"32206811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRSF1 inhibits autophagosome formation by (1) promoting splicing of Bcl-xL long isoform which binds Beclin1 and dissociates the Beclin1-PIK3C3 complex, and (2) directly interacting with PIK3C3 to disrupt Beclin1-PIK3C3 interaction. SRSF1 itself is degraded by starvation/oxidative stress-induced autophagy through interaction with LC3-II, creating a positive feedback loop.\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown; LC3-II autophagy markers; RT-PCR splicing assay; starvation and oxidative stress assays; xenograft model\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing direct PIK3C3 binding, splicing assay, multiple functional readouts, in vivo model\",\n      \"pmids\": [\"33664238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRSF1 directly binds MALAT1 lncRNA and facilitates its RNA stability in glioma cells. SRSF1 is the most highly expressed SRSF in 9 tumor types, and it regulates the cell cycle in glioma by stabilizing NEAT1 lncRNA through direct binding.\",\n      \"method\": \"RNA immunoprecipitation; RNA stability assay; SRSF1 knockdown; NEAT1 knockdown cell cycle analysis\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and RNA stability assay, single lab\",\n      \"pmids\": [\"31200124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRSF1 directly binds and promotes export of NKILA lncRNA via clustered SRSF1/SRSF7 binding sites in CAR-N region, facilitating TREX/UAP56/ALYREF assembly and TAP-dependent nuclear export; NKILA lacking CAR-N is unable to inhibit breast cancer cell migration.\",\n      \"method\": \"RNA pull-down; mass spectrometry; siRNA screening; EMSA; RNA and protein immunoprecipitation; knock-in models\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods (MS, EMSA, RIP), knock-in validation, single lab\",\n      \"pmids\": [\"34096602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRPK1/2 phosphorylate SRSF1, promoting its nuclear translocation, and PP1α opposes this by dephosphorylating SRSF1. The balance of SRSF1 phosphorylation/subcellular localization by SRPK1/2 and PP1α controls alternative splicing of MKNK2 in colon adenocarcinoma cells, with high nuclear SRSF1 promoting MKNK2b (oncogenic) isoform.\",\n      \"method\": \"Immunohistochemistry; western blot; siRNA knockdown; RT-PCR splicing assay; xenograft model; phosphorylation analysis\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic manipulation of kinase/phosphatase with splicing readout and subcellular localization, single lab\",\n      \"pmids\": [\"33602301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRSF1 conditional deletion in thymocytes blocks the transition of immature TCRβhi thymocytes to mature ones. SRSF1 directly binds and regulates alternative splicing of Irf7 and Il27ra in response to type I interferon signaling; forced IRF7 expression rectifies the maturation defects of SRSF1-deficient thymocytes.\",\n      \"method\": \"Conditional Srsf1 KO mouse; flow cytometry; RNA-seq; SRSF1-RNA binding assay; IRF7 rescue overexpression\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO, RNA-seq, direct binding assay, genetic rescue — multiple orthogonal methods, single lab\",\n      \"pmids\": [\"33863728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Conditional deletion of SRSF1 in Treg cells causes profound autoimmunity; mechanistically, loss of SRSF1 elevates glycolytic metabolism and mTORC1 activity, and increases proinflammatory cytokine production, controlling Treg cell plasticity.\",\n      \"method\": \"Treg-specific Srsf1 conditional KO mouse; flow cytometry; metabolic assays (glycolysis); mTORC1 pathway immunoblot; cytokine measurement\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with metabolic and signaling pathway readouts, single lab\",\n      \"pmids\": [\"34233194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The RNA binding protein RNPS1, when overexpressed, suppresses DNA fragmentation, hypermutation, and G2 arrest caused by ASF/SF2 (SRSF1) depletion. This suggests RNPS1 functions together with ASF/SF2 to form RNP complexes on nascent transcripts and prevent R-loop formation; ASF/SF2 depletion does not affect RNPS1 expression, and RNPS1 cannot compensate for ASF/SF2 splicing function.\",\n      \"method\": \"RNAi depletion; RNPS1 overexpression suppressor experiment; DNA damage assays (HMW fragmentation, mutation frequency); cell cycle analysis\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic suppressor experiment with defined cellular phenotypes, single lab\",\n      \"pmids\": [\"17959926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRMT1 methylates SRSF1; this methylation is critical for SRSF1 phosphorylation, SRSF1 binding to RNA, and exon inclusion. PRMT1 overexpression in breast tumors correlates with increased SRSF1 arginine methylation and aberrant exon inclusion. A selective PRMT1 inhibitor (iPRMT1) suppresses SRSF1 methylation, exon inclusion, and breast cancer cell growth; combination with SRSF1 phosphorylation inhibitors shows additive growth suppression.\",\n      \"method\": \"PRMT1 methylome profiling; in vitro methylation assay; RNA binding assay; RT-PCR splicing; pharmacological inhibition (iPRMT1, SRPK inhibitor); cell proliferation assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro methylation reconstitution with RNA binding assay, pharmacological manipulation, single lab multiple methods\",\n      \"pmids\": [\"37938975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SRSF1 activates MAPK signaling in pancreas by upregulating IL1R1 through alternative-splicing-regulated mRNA stability. In phenotypically normal epithelial cells expressing KRASG12D, SRSF1 protein is destabilized through a negative feedback mechanism. Hyperactive MYC overcomes this feedback, facilitating PDAC tumorigenesis. Increased SRSF1 is sufficient to induce pancreatitis and accelerate KRASG12D-mediated PDAC.\",\n      \"method\": \"Conditional transgenic/KO mouse models; pancreas organoids; RNA-seq; RT-PCR; mRNA stability assay; MAPK pathway immunoblot\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple mouse models, organoids, mechanistic pathway validation with multiple orthogonal methods\",\n      \"pmids\": [\"37098965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Haploinsufficiency of SRSF1 causes a syndromic neurodevelopmental disorder. Loss-of-function and pathogenic missense variants impair SRSF1 splicing activity as demonstrated by in vivo splicing assay in Drosophila, and correlate with a detectable DNA methylation episignature in blood-derived DNA from affected individuals.\",\n      \"method\": \"In vivo Drosophila splicing assay; in silico structural modeling; DNA methylation episignature analysis; genotype-phenotype analysis in 17 individuals\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo Drosophila functional assay with orthogonal epigenetic confirmation, single study\",\n      \"pmids\": [\"37071997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RNF125 E3 ubiquitin ligase physically interacts with SRSF1 (identified by mass spectrometry and co-immunoprecipitation) and accelerates proteasome-mediated degradation of SRSF1, thereby inhibiting the SRSF1/ERK signaling pathway and suppressing HCC proliferation and metastasis.\",\n      \"method\": \"Mass spectrometry; co-immunoprecipitation; ubiquitin ladder assay; proteasome inhibition; siRNA/overexpression; xenograft model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, and functional rescue, single lab\",\n      \"pmids\": [\"37142680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SRSF1 physically interacts with FANCD2 (identified by Co-IP); SRSF1 stimulates FANCD2 monoubiquitination in an RNA-dependent fashion. FANCD2 monoubiquitination is required for assembly of the SRSF1-NXF1 nuclear export complex and mRNA export. Cancer-associated SRSF1 mutants fail to interact with FANCD2, leading to deficient FANCD2 monoubiquitination, decreased mRNA export, and R-loop accumulation.\",\n      \"method\": \"Co-immunoprecipitation; monoubiquitination assay; mRNA export assay; R-loop detection (S9.6); SRSF1 cancer mutant analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, functional ubiquitination and export assays, mutant analysis — multiple orthogonal methods, single lab\",\n      \"pmids\": [\"38165804\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SRSF1 (SF2/ASF) is a multifunctional SR protein whose RS domain phosphorylation state (controlled sequentially by SRPK1, Clk/Sty, AMPK, Akt, and PP1α, and additionally by arginine methylation via PRMT1) governs its assembly into nuclear speckles, RNA-binding specificity, and activity in splicing; its two RRMs recognize purine-rich ESEs and CN motifs to promote exon inclusion or skipping in a position-dependent manner, while the inter-RRM linker engages the mRNA export factor NXF1/TAP; beyond splicing, SRSF1 shuttles to the cytoplasm to regulate mRNA stability and translation (including mTORC1-dependent translation), facilitates miRNA maturation via Drosha, promotes NMD by recruiting UPF1 downstream of PTCs, suppresses R-loop formation to maintain genome integrity, acts as a SUMO E3-like ligase by interacting with Ubc9 and PIAS1, stabilizes p53 by engaging the RPL5-MDM2 complex, and is subject to ubiquitin-mediated proteasomal degradation by RNF125, with its haploinsufficiency causing a neurodevelopmental syndrome and its overexpression driving oncogenesis through multiple downstream splicing targets including S6K1, MNK2, BIN1, Ron/DeltaRon, caspase-9, and MYO1B.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SRSF1 (SF2/ASF) is a prototypical SR protein that functions as an essential pre-mRNA splicing factor, originally purified as a ~33 kDa activity required for 5' splice site cleavage, lariat formation, and assembly of the earliest prespliceosome complex [#0]. Its two RRMs recognize purine-rich exonic splicing enhancers and CN motifs through a cooperative, bimodal binding mode, with RRM2 employing a noncanonical surface and the flexible inter-RRM linker permitting RNA engagement on both sides of the RRM2 site [#1, #12, #38]; genome-wide binding and positional modeling established that SRSF1 occupancy near the 5' splice site promotes exon inclusion whereas 3'-proximal binding can drive skipping or inclusion [#14, #29]. SRSF1 activity is governed by the phosphorylation state of its RS domain: SRPK1/2 phosphorylate the N-terminal RS region to drive nuclear-speckle assembly and nuclear translocation, Clk/Sty phosphorylates the C-terminal RS region to release it from speckles, and PP1—docked on RRM1—dephosphorylates it, with both phosphorylation and subsequent dephosphorylation being required across the splicing cycle [#2, #10, #34, #46]; additional control comes from AMPK and Akt phosphorylation within the RRM and from PRMT1-mediated arginine methylation, which together tune RNA binding and splice-target selection [#20, #37, #50]. Beyond nuclear splicing, SRSF1 shuttles to the cytoplasm to regulate mRNA stability and translation, including mTORC1-dependent translation, and this shuttling is required for ciliogenesis [#16, #40]; it engages the mRNA export factor NXF1/TAP via its inter-RRM linker, a complex whose assembly depends on SRSF1-stimulated FANCD2 monoubiquitination and which is exploited for pathological C9ORF72 repeat-RNA export [#12, #31, #54]. SRSF1 additionally promotes miR-7 maturation via Drosha, stimulates UPF1-dependent nonsense-mediated decay, suppresses R-loop formation to protect genome integrity, and acts as a SUMO pathway regulator interacting with Ubc9 and PIAS1 [#17, #32, #39, #18]. Acting downstream of MYC, which transcriptionally activates it, SRSF1 is a potent oncoprotein whose overexpression transforms cells through splicing of targets including BIN1, MNK2, S6K1, Ron, caspase-9, and MYO1B and through mTORC1 activation, while it conversely enforces p53-dependent senescence via the RPL5-MDM2 complex and is degraded by the E3 ligase RNF125 [#13, #23, #15, #22, #24, #53]. SRSF1 is also essential for T-cell homeostasis and immune tolerance through an SRSF1-PTEN-mTORC1 axis [#36]. Haploinsufficiency of SRSF1 causes a syndromic neurodevelopmental disorder with a defined DNA methylation episignature [#52].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established SRSF1 as a bona fide splicing factor by showing a purified ~33 kDa protein is necessary and sufficient to reconstitute early spliceosome assembly and 5' splice site usage, defining the core activity all later work builds on.\",\n      \"evidence\": \"Protein purification to near homogeneity with in vitro splicing complementation and RNA annealing assays in HeLa extracts\",\n      \"pmids\": [\"2145194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the RNA sequence specificity\", \"Did not assign roles to individual domains\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Defined the RNA-recognition logic by showing SRSF1's RRMs cooperatively bind a distinct purine-rich motif and that high-affinity sites organized as an exonic splicing enhancer activate splicing, linking sequence recognition to functional splice-site selection.\",\n      \"evidence\": \"SELEX, full-length binding assays, and in vitro splicing in S100 extracts\",\n      \"pmids\": [\"7543047\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the cooperative binding not resolved\", \"Position-dependent enhancer/silencer effects not yet defined\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed that SRSF1 activity is bidirectionally controlled by RS-domain phosphorylation, with phosphorylation needed for assembly and dephosphorylation required for the first catalytic transesterification, framing the protein as a phospho-switch in splicing.\",\n      \"evidence\": \"In vitro splicing with defined phospho-states and thiophosphorylation to block dephosphorylation\",\n      \"pmids\": [\"9404896\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the responsible kinases and phosphatases\", \"Did not connect phospho-state to subcellular localization\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified SRPK1 as a direct physiological kinase for SRSF1, showing bacterially co-expressed phosphorylated SRSF1 is soluble and splicing-competent, establishing the upstream enzyme controlling the phospho-switch.\",\n      \"evidence\": \"Co-expression in E. coli with in vitro splicing and solubility assays\",\n      \"pmids\": [\"10666475\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Site specificity within the RS domain not mapped\", \"Relationship to speckle localization not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved how sequential kinases partition SRSF1 between subnuclear compartments, showing SRPK1 phosphorylates the N-terminal RS region for speckle assembly and Clk/Sty the C-terminal region for release, mechanistically coupling phosphorylation to localization.\",\n      \"evidence\": \"SRPK1-SR peptide crystal structure, kinase assays with deletion mutants, and immunofluorescence localization\",\n      \"pmids\": [\"16209947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address the opposing phosphatase\", \"In vivo consequences of mislocalization not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the structural RNA-binding mode of RRM2 and revealed that the inter-RRM linker is a binding site for the export factor TAP that competes with RNA, providing the first molecular link between SRSF1 and mRNA export.\",\n      \"evidence\": \"NMR structure of RRM2 with RNA and TAP binding/competition assays\",\n      \"pmids\": [\"17668007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular export targets not yet identified\", \"RRM1 recognition mode still undefined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated that SRSF1 is an oncoprotein, showing overexpression transforms cells and forms tumors via splicing of BIN1, MNK2, and S6K1, converting a housekeeping splicing factor into a driver of malignancy.\",\n      \"evidence\": \"Transformation and xenograft assays with shRNA knockdown, RT-PCR splicing, and isoform-rescue epistasis\",\n      \"pmids\": [\"17310252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling SRSF1 levels in cancer unknown\", \"Full target spectrum not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapped the genome-wide SRSF1 binding landscape, showing thousands of purine-rich sites enriched near splice sites and over-represented on RNA-processing transcripts, scaling the binding logic to the transcriptome.\",\n      \"evidence\": \"CLIP-seq in HEK cells with motif analysis\",\n      \"pmids\": [\"19116412\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish positional rules for inclusion versus skipping\", \"Functional consequence of most sites untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected SRSF1 oncogenesis to a specific signaling output by showing it activates mTORC1 independently of Akt and that this is essential for transformation, linking splicing-factor function to translational control.\",\n      \"evidence\": \"Phospho-immunoblot, genetic knockdown of mTOR components, and rapamycin in focus-formation and xenograft assays\",\n      \"pmids\": [\"18832178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct splicing/mRNA target driving mTORC1 not pinpointed\", \"Mechanism of Akt bypass unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that SRSF1 negatively autoregulates its own abundance through unproductive splicing coupled to NMD and RRM2/3'UTR-mediated translational repression, and that a miR-7 feedback loop reinforces this, defining how a potent oncoprotein is kept in check.\",\n      \"evidence\": \"Isoform analysis, polysome fractionation, mutagenesis, Dicer knockdown, RIP, Drosha cleavage and 3'UTR reporter assays\",\n      \"pmids\": [\"20139984\", \"20385090\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How feedback is overridden in cancer not resolved here\", \"miRNA-independent translational repression mechanism incompletely defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended SRSF1 function beyond splicing by showing it stimulates global SUMO conjugation via Ubc9 and PIAS1 through its RRM2, identifying a moonlighting role in post-translational modification.\",\n      \"evidence\": \"Co-IP, knockdown/overexpression, in vitro and in vivo sumoylation, and domain mapping\",\n      \"pmids\": [\"20805487\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic basis of E3-like activity not structurally defined\", \"Physiological SUMO substrate spectrum incomplete\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed SRSF1 in the MYC oncogenic program from both directions, showing MYC transcriptionally activates SRSF1 and that SRSF1 cooperates with MYC to transform cells, establishing a feed-forward oncogenic circuit.\",\n      \"evidence\": \"ChIP, promoter reporters, MYC/SRSF1 knockdown, orthotopic transplantation, and 3D culture with MKNK2/TEAD1/BIN1/BIM splicing readouts\",\n      \"pmids\": [\"22545246\", \"22245967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of each splice target to transformation unclear\", \"Tissue specificity of the circuit not mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed a tumor-suppressive arm of SRSF1 by showing it is a necessary component of an RPL5-MDM2 complex that stabilizes p53 and triggers oncogene-induced senescence, explaining a fail-safe against SRSF1-driven transformation.\",\n      \"evidence\": \"Co-IP of the endogenous complex, p53 stability and senescence assays in primary fibroblasts\",\n      \"pmids\": [\"23478443\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Splicing-independence of this role not fully delineated\", \"How cancers escape this senescence response unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved long-standing discrepancies by deriving positional rules from transcriptome-wide data, showing 5'-proximal SRSF1 binding favors inclusion while 3'-proximal binding can drive skipping or inclusion, and validated a downstream oncogenic isoform.\",\n      \"evidence\": \"RNA-seq in 3D culture, de novo motif discovery, Bayesian positional modeling, and CASC4 isoform overexpression\",\n      \"pmids\": [\"26431027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of position-dependent outcomes not addressed\", \"Determinants of skip-versus-include at 3' sites unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined two additional post-transcriptional roles, showing SRSF1 stimulates UPF1-dependent NMD downstream of premature termination codons by recruiting UPF1 while bypassing UPF2, broadening its surveillance function.\",\n      \"evidence\": \"RIP, tethering and NMD reporter assays, and UPF2/EJC depletion\",\n      \"pmids\": [\"29768215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of UPF1 recruitment unknown\", \"Relationship to EJC-dependent NMD not fully separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Solved the structural basis for the opposing phosphatase, mapping the PP1 docking surface on RRM1 and showing its disruption lowers RS phosphorylation, redistributes SRSF1 from speckles, and shifts splicing, completing the kinase-phosphatase regulatory circuit.\",\n      \"evidence\": \"NMR, site-directed mutagenesis, in vitro dephosphorylation, FRAP, and RT-PCR splicing\",\n      \"pmids\": [\"30185622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo phenotype of PP1 uncoupling not tested\", \"Crosstalk with SRPK/Clk timing unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed that AMPK phosphorylates SRSF1 within the RRM at Ser133 to suppress RNA binding without altering localization, demonstrating that metabolic signaling can directly retune splice-site selection independently of the RS-domain switch.\",\n      \"evidence\": \"In vitro kinase assay, S133A mutagenesis, RNA-protein interaction and Ron splicing assays\",\n      \"pmids\": [\"32453427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide consequences of Ser133 phosphorylation untested\", \"Physiological metabolic triggers in vivo not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established that cytoplasmic shuttling of SRSF1 is physiologically required, showing nuclear-retained SRSF1 reduces translation of multiciliogenesis proteins and causes ciliary defects in mice, decoupling its cytoplasmic translational role from nuclear splicing.\",\n      \"evidence\": \"Nuclear-retention knock-in mouse with developmental phenotyping, polysome/translation assays, proteomics, and cilia EM\",\n      \"pmids\": [\"34338635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific cytoplasmic mRNA targets driving ciliogenesis not enumerated\", \"Mechanism of translational selectivity unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated SRSF1 maintains genome integrity by suppressing R-loops, showing hepatocyte deletion causes RNA-DNA hybrid accumulation, DNA damage, and NASH-like pathology, linking its RNA processing role to genome protection in vivo.\",\n      \"evidence\": \"Hepatocyte-specific Srsf1 knockout mouse with S9.6 R-loop imaging, transcriptome/proteome sequencing, and eCLIP\",\n      \"pmids\": [\"36759613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical mechanism of R-loop prevention not defined\", \"Contribution of co-factors like RNPS1 not integrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a single-molecule, exon-independent recruitment of SRSF1 by U1 snRNP via contacts to U1 snRNA stem-loop 3, providing a mechanistic basis for U1-mediated exon definition beyond enhancer binding.\",\n      \"evidence\": \"Single-molecule fluorescence with structural cross-linking and stem-loop 3 mutagenesis\",\n      \"pmids\": [\"34779515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality across endogenous exons not established\", \"Interplay with enhancer-dependent recruitment unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established SRSF1 as a non-redundant controller of T-cell homeostasis and tolerance, showing T-cell Srsf1 deletion causes autoimmunity via a PTEN-mTORC1 axis rescuable by rapamycin or SRSF1 re-expression.\",\n      \"evidence\": \"T-cell conditional knockout mice with flow cytometry, PTEN/mTORC1 immunoblots, rapamycin, and overexpression rescue\",\n      \"pmids\": [\"31487268\", \"33863728\", \"34233194\", \"32206811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct splice/stability targets controlling PTEN not fully mapped\", \"Cell-type-specific target sets across T-cell subsets incompletely defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked SRSF1 dosage to human disease at both extremes, identifying haploinsufficiency as the cause of a syndromic neurodevelopmental disorder with a methylation episignature, while parallel work showed RNF125-mediated degradation and FANCD2-dependent export tie SRSF1 to oncogenic and genome-stability pathways.\",\n      \"evidence\": \"Drosophila in vivo splicing assays and methylation episignature in patients; Co-IP, ubiquitination, monoubiquitination, and mRNA export/R-loop assays\",\n      \"pmids\": [\"37071997\", \"37142680\", \"38165804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype mechanism of the neurodevelopmental syndrome incompletely defined\", \"Structural basis of the SRSF1-FANCD2 interaction unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified PRMT1-mediated arginine methylation as an upstream determinant of SRSF1 phosphorylation, RNA binding, and exon inclusion, adding a methylation layer to the regulatory hierarchy with therapeutic implications in breast cancer.\",\n      \"evidence\": \"Methylome profiling, in vitro methylation, RNA binding, splicing assays, and pharmacological inhibition with iPRMT1 and SRPK inhibitors\",\n      \"pmids\": [\"37938975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Methylated residues' structural impact not resolved\", \"Hierarchy with phosphorylation timing not fully ordered\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multilayered modification code (SRPK/Clk phosphorylation, AMPK/Akt RRM phosphorylation, PRMT1 methylation, PP1 dephosphorylation) is integrated in real time to select specific splice, export, decay, and translation targets in a given cell state remains unresolved.\",\n      \"evidence\": \"No single study in the timeline integrates all modification inputs with target selection in vivo\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking modification state to target choice\", \"Cell-type-specific target rewiring not mechanistically explained\", \"Structural basis of how modifications alter RRM/RS function incompletely defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 12, 14, 38, 41]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 2, 29, 32]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [16, 19, 40]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [12, 31, 32, 54]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [25, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [10, 34]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10, 25, 46]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [16, 40, 46]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2, 16, 17, 29, 32]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [25, 27]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [12, 31, 45, 54]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [13, 22, 35, 51, 52, 53]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [36, 42, 47, 48]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [39, 49, 54]}\n    ],\n    \"complexes\": [\n      \"nuclear speckles\",\n      \"RPL5-MDM2 complex\",\n      \"7SK snRNP\",\n      \"TREX/UAP56/ALYREF export complex\"\n    ],\n    \"partners\": [\n      \"NXF1\",\n      \"SRPK1\",\n      \"PP1\",\n      \"Ubc9\",\n      \"PIAS1\",\n      \"UPF1\",\n      \"FANCD2\",\n      \"RNF125\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}