{"gene":"SRSF2","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":1992,"finding":"SC35 (SRSF2) was isolated as a splicing factor required for the first step of the splicing reaction and for spliceosome assembly; its cDNA revealed it contains an RNP-type RNA binding motif and a C-terminal SR domain, making it a member of the SR protein family.","method":"cDNA cloning, in vitro splicing reconstitution assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical reconstitution of splicing activity, foundational cloning paper replicated by multiple subsequent studies","pmids":["1373910"],"is_preprint":false},{"year":1992,"finding":"Recombinant SC35 can reconstitute splicing activity in S100 extracts and in SC35-immunodepleted nuclear extracts; SC35 favors proximal 5' and 3' splice sites, an effect antagonized by hnRNP A1.","method":"In vitro splicing reconstitution assay with recombinant proteins and immunodepleted extracts","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with recombinant proteins, replicated across labs","pmids":["1454802"],"is_preprint":false},{"year":1995,"finding":"SC35 and ASF/SF2 have distinct, functionally significant RNA binding specificities determined by SELEX; the arginine-serine region is not the major determinant of specificity. Unlike ASF/SF2, a SC35 high-affinity binding site element did not function as a splicing enhancer in S100 complementation assays.","method":"SELEX, RNA binding assays, in vitro splicing complementation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — SELEX plus functional splicing assay, multiple orthogonal methods in one study","pmids":["7543047"],"is_preprint":false},{"year":1997,"finding":"SC35 can functionally substitute for U2AF65 in reconstituting pre-mRNA splicing in U2AF-depleted HeLa nuclear extracts, in a substrate-specific and U1 snRNP-dependent manner, demonstrating a U2AF-independent pathway for U2 snRNP recruitment.","method":"Affinity depletion of U2AF from nuclear extracts, in vitro splicing reconstitution with recombinant SC35","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with depleted extracts and recombinant protein, clean mechanistic demonstration","pmids":["8990173"],"is_preprint":false},{"year":2000,"finding":"A novel ESE motif recognized by SC35 under splicing conditions was identified by in vitro functional SELEX; SC35-selected sequences promote splicing in nuclear extract or S100 complemented by SC35 but not by SF2/ASF, demonstrating distinct and functional RNA sequence specificity.","method":"In vitro SELEX under splicing conditions, in vitro splicing assays in S100 and nuclear extracts","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — SELEX plus functional splicing validation with multiple substrates and controls","pmids":["10629063"],"is_preprint":false},{"year":2001,"finding":"SC35 autoregulates its own expression by activating specific alternative splicing events in the 3' UTR of its own pre-mRNA, producing unstable mRNA isoforms subject to mRNA surveillance; this effect is specific to SC35 and not shared by ASF/SF2 or 9G8.","method":"Overexpression in HeLa cells, in vitro splicing with recombinant SR proteins, siRNA knockdown, mRNA stability assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro splicing reconstitution plus in vivo overexpression and stability assays, specific to SC35","pmids":["11285241"],"is_preprint":false},{"year":2001,"finding":"Cre-mediated conditional deletion of SC35 in the thymus causes a defect in T cell maturation and alters alternative splicing of CD45 (a receptor tyrosine phosphatase), establishing SC35 as a physiological regulator of a T cell-specific splicing pathway.","method":"Conditional knockout mouse (Cre-lox), RT-PCR for CD45 isoforms","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with defined molecular phenotype (CD45 splicing), replicated in vivo","pmids":["11239462"],"is_preprint":false},{"year":2003,"finding":"GSK-3 phosphorylates SC35 in vitro (on a peptide from its SR domain requiring priming phosphorylation) and affects its intranuclear distribution; GSK-3 inhibition in neurons redistributes SC35 to nuclear speckles and increases tau exon 10 inclusion.","method":"In vitro kinase assay with recombinant GSK-3β, immunoprecipitation of SC35, immunofluorescence, RT-PCR for tau splicing","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay plus cell-based splicing change, single lab","pmids":["14602710"],"is_preprint":false},{"year":2004,"finding":"Tissue-specific ablation of SC35 in the heart causes dilated cardiomyopathy preceded by downregulation of cardiac ryanodine receptor 2 (RyR2), with mutant cardiomyocytes showing frequency-dependent excitation-contraction coupling defects.","method":"Conditional knockout mouse (MLC-2v-Cre), microarray, RT-PCR, calcium imaging","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with specific molecular target (RyR2 downregulation) and functional readout","pmids":["14963485"],"is_preprint":false},{"year":2005,"finding":"SC35 is responsible for aberrant splicing of E1alpha pyruvate dehydrogenase mRNA caused by a disease mutation: the mutation increases SC35 binding to a cryptic splice donor, and siRNA-mediated reduction of SC35 in patient fibroblasts abolishes the aberrant splice product.","method":"RNA binding assays, overexpression, siRNA knockdown in patient fibroblasts, RT-PCR","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA rescue in patient cells plus binding assay, multiple orthogonal methods","pmids":["15798212"],"is_preprint":false},{"year":2007,"finding":"Loss of SC35 in mouse embryonic fibroblasts induces G2/M cell cycle arrest and genomic instability via p53 hyperphosphorylation (linked to ATM activation) and hyperacetylation (attributed to increased p300 expression and aberrant SirT1 splicing); SC35 also controls cell proliferation during pituitary gland development but is dispensable in mature cardiomyocytes.","method":"Conditional knockout mouse, cell cycle analysis, immunoblotting for p53 modifications, RT-PCR for SirT1 splicing","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with mechanistic pathway placement via p53 modifications and specific splicing target","pmids":["17526736"],"is_preprint":false},{"year":2008,"finding":"SC35 depletion induces RNA Pol II accumulation within gene bodies and attenuated transcriptional elongation, correlated with defective P-TEFb recruitment and dramatically reduced CTD Ser2 phosphorylation; recombinant SC35 rescues this elongation defect in nuclear run-on experiments.","method":"siRNA depletion, ChIP for Pol II and P-TEFb, nuclear run-on assay with recombinant SC35","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — recombinant protein rescue in nuclear run-on plus ChIP, multiple orthogonal methods","pmids":["18641664"],"is_preprint":false},{"year":2008,"finding":"E2F1 transcriptionally upregulates SC35 (SRSF2) expression; SC35 is required for E2F1-induced switching of alternative splicing of apoptotic genes (c-FLIP, caspase-8, caspase-9, Bcl-x) toward pro-apoptotic splice variants and for apoptosis in response to DNA-damaging agents.","method":"ChIP for E2F1 at SRSF2 promoter, siRNA knockdown of SC35, RT-PCR for splice isoforms, apoptosis assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP plus siRNA with defined splicing readouts, multiple targets validated","pmids":["18806759"],"is_preprint":false},{"year":2009,"finding":"SC35 promotes tau exon 10 inclusion by binding to a SC35-like exonic splicing enhancer on tau pre-mRNA; mutation of this element abolishes both SC35 binding and exon inclusion. Dyrk1A phosphorylates SC35 in vitro and interacts with SC35 in cells, and overexpression of Dyrk1A suppresses SC35's ability to promote tau exon 10 inclusion.","method":"Co-immunoprecipitation, in vitro kinase assay, minigene splicing assay, mutation analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay plus RIP plus minigene mutagenesis, multiple orthogonal methods","pmids":["21470964"],"is_preprint":false},{"year":2009,"finding":"The SC35 terminal intron self-regulation involves exonic splicing enhancer elements in the last exon that respond specifically to SC35; hnRNP H and TDP-43 antagonize SC35 binding to the terminal exon and repress SC35 terminal 3' splice site usage.","method":"Minigene splicing assays, RNA binding competition assays, in vitro and in cellulo splicing","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and cell-based splicing assays, single lab with multiple constructs","pmids":["19965769"],"is_preprint":false},{"year":2010,"finding":"Tip60 acetyltransferase acetylates SRSF2 on lysine 52 (within the RRM), promoting its proteasomal degradation; HDAC6 deacetylase counters this acetylation and acts as a positive regulator of SRSF2 protein level. Tip60 also downregulates SRSF2 phosphorylation by inhibiting nuclear translocation of SRPK1 and SRPK2. This acetylation/phosphorylation network controls caspase-8 pre-mRNA splicing and cell fate in response to cisplatin.","method":"In vitro acetylation assay, site-directed mutagenesis (K52), co-immunoprecipitation, siRNA knockdown, RT-PCR for caspase-8 isoforms","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro acetylation with mutagenesis plus functional splicing readout, multiple orthogonal methods","pmids":["21157427"],"is_preprint":false},{"year":2011,"finding":"The solution NMR structure of SRSF2 RRM bound to 5'-UCCAGU-3' and 5'-UGGAGU-3' RNA reveals a sandwich-like structure; SRSF2 binds both sequences equally by flipping the two central C or G bases into anti or syn conformation. The L3 loop is crucial for RNA binding (NMR/mutagenesis). The high-affinity consensus is 5'-SSNG-3' (S=C/G), validated by in vitro and in vivo splicing assays.","method":"NMR structure determination, mutagenesis, ITC/binding assays, in vitro and in vivo splicing assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure plus mutagenesis plus functional validation, multiple orthogonal methods in one study","pmids":["22002536"],"is_preprint":false},{"year":2011,"finding":"The solution structure of the free SRSF2 RRM (residues 9-101) was determined; unlike other SR proteins, SRSF2 has a longer L3 loop and lacks the conserved aromatic residue in RNP2. The L3 loop (in addition to canonical β1/β3 strands) is essential for RNA binding, shown by NMR chemical shift perturbation and mutagenesis; RNA 5'-AGCAGAGUA-3' binds with Kd = 61 nM.","method":"NMR structure determination, ITC, site-directed mutagenesis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure plus mutagenesis plus quantitative binding measurement","pmids":["22140111"],"is_preprint":false},{"year":2011,"finding":"SC35 binds tau exon 10 mRNA via the SC35-like element and stabilizes tau mRNA (specifically exon 10-containing isoforms) without affecting tau transcription, thereby promoting tau protein expression.","method":"RNA immunoprecipitation (RIP), mRNA stability assay, RT-PCR, overexpression","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RIP plus mRNA stability assay, single lab, two orthogonal methods","pmids":["21333649"],"is_preprint":false},{"year":2013,"finding":"SRSF2 promotes splicing and transcription of exon 11-included isoform of the Ron proto-oncogene by binding to a CGAG sequence on exon 11; mutation of this sequence abolishes both physical interaction and splicing promotion.","method":"Knockdown/overexpression, RT-PCR, RNA pull-down/mutation analysis","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — mutagenesis of binding site with functional readout, single lab","pmids":["25220236"],"is_preprint":false},{"year":2015,"finding":"SRSF2 mutations (e.g., P95H) alter SRSF2's sequence-specific RNA binding activity, changing recognition of specific ESE motifs to drive recurrent mis-splicing of hematopoietic regulators including EZH2 (triggering NMD), thereby impairing hematopoietic differentiation in vivo.","method":"Conditional knockin mouse, RNA-seq, in vivo differentiation assays, splicing reporter assays","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockin mouse model with RNA-seq and functional hematopoietic phenotype, independently replicated","pmids":["25965569"],"is_preprint":false},{"year":2015,"finding":"SRSF2 P95H mutation introduced by CRISPR into K562 cells alters RNA binding affinity in a motif-specific manner: mutant SRSF2 binds UCCAG sites more tightly and UGGAG sites less tightly than wild-type, causing corresponding increased or decreased exon inclusion; protein-protein interactions with key splicing factors are unaffected by the mutation.","method":"CRISPR knockin, RNA gel shift assays, RNA-seq for splicing changes, co-immunoprecipitation","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — isogenic CRISPR model plus in vitro RNA binding assays with mutagenesis, multiple orthogonal methods","pmids":["26261309"],"is_preprint":false},{"year":2015,"finding":"Ablation of SRSF2 in the hematopoietic lineage causes embryonic lethality with enhanced apoptosis and decreased hematopoietic stem/progenitor cells; adult conditional knockout shows decreased LSK cells; MDS-associated P95H and P95-R102 deletion mutations cause significant changes in alternative splicing of genes enriched in cancer and apoptosis.","method":"Conditional knockout mouse (Mx1-Cre), RNA-seq for splicing changes, HSPC flow cytometry","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with defined cellular and molecular phenotypes, multiple splice targets identified","pmids":["26124281"],"is_preprint":false},{"year":2017,"finding":"SRSF2 binding within an alternative exon is associated with its inclusion, whereas SRSF2 binding in a flanking constitutive exon is associated with exclusion of the alternative exon; SRSF2 regulates alternative splicing driving hepatocellular carcinoma progression.","method":"CLIP-seq/RNA-seq, knockdown/overexpression, RT-PCR for splice isoforms","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CLIP-seq binding mapped to splicing outcomes, single lab","pmids":["28082404"],"is_preprint":false},{"year":2017,"finding":"Liver-specific deletion of SRSF2 (but not SRSF1) causes acute liver failure; SRSF2 governs splicing of multiple stress-induced cell death pathway genes and acts as a transcription activator required for expression of transcription factors controlling energy homeostasis and bile acid metabolism.","method":"Liver-specific conditional knockout mouse (Cre-lox), RNA-seq, histology, biochemical assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO with global RNA-seq and defined metabolic/splicing phenotypes","pmids":["27022105"],"is_preprint":false},{"year":2018,"finding":"SRSF2P95H mutation globally alters RNA binding (HITS-CLIP) and splicing; most differential binding events do not directly translate to local exon splicing changes, suggesting indirect/cascade effects. SRSF2P95H targets are enriched in RNA processing genes including hnRNP and SR family members; aberrant splicing of HNRNPA2B1 was shown to impair hematopoietic differentiation in vivo.","method":"HITS-CLIP, RNA-seq, in vivo hematopoietic differentiation assay","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Strong — HITS-CLIP plus RNA-seq plus in vivo functional validation, multiple orthogonal methods","pmids":["29858584"],"is_preprint":false},{"year":2018,"finding":"Conditional knockin mice expressing Srsf2 P95H heterozygously from endogenous locus develop progressive transplantable MDS/MPN with myeloid bias, monocytosis, and dysplasia during native hematopoiesis (no transplant stress); the mutation must occur in HSC-containing populations to promote disease.","method":"Conditional knockin mouse (multiple Cre lines), transplantation assay, RNA-seq","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — physiological knockin model with defined HSC phenotype and RNA splicing changes, replicated across Cre lines","pmids":["29903888"],"is_preprint":false},{"year":2019,"finding":"SRSF2 associates with the P300/CBP acetyltransferase complex and alters H3K27Ac levels near immune checkpoint gene transcription start sites, thereby influencing STAT3 recruitment to these promoters and regulating transcription of multiple immune checkpoint molecules (PD-1, TIM-3, etc.) in exhausted T cells.","method":"Co-immunoprecipitation, ChIP for H3K27Ac and STAT3, siRNA knockdown, RT-PCR","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus ChIP plus functional knockdown, single lab","pmids":["31838573"],"is_preprint":false},{"year":2020,"finding":"SRSF2 Pro95 hot-spot mutations enhance mRNA decay (NMD) through sequence-specific RNA binding and splicing; mutant SRSF2 enhances deposition of exon junction complexes (EJCs) downstream from PTCs via RNA-mediated molecular interactions, recruiting NMD factors. Antisense oligonucleotide blocking of EJC deposition restores PTC-containing transcript levels.","method":"RNA-seq, EJC deposition assays, antisense oligonucleotide rescue, splicing reporter assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple mechanistic assays (EJC deposition, ASO rescue, splicing) with isogenic mutant cells","pmids":["32001512"],"is_preprint":false},{"year":2020,"finding":"SFPQ, in complex with p54nrb, binds SRSF2 under platinum treatment and decreases SRSF2 binding to caspase-9 RNA, favoring expression of its antiapoptotic alternatively spliced form and contributing to chemoresistance.","method":"Co-immunoprecipitation (SFPQ/p54nrb/SRSF2 complex), RNA immunoprecipitation for caspase-9, siRNA knockdown, RT-PCR for splice isoforms","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal Co-IP plus RIP with functional splicing readout, single lab","pmids":["32332923"],"is_preprint":false},{"year":2023,"finding":"SRSF2 functions as a reader of m5C RNA modification; structurally identified residues mediate m5C recognition. NSUN2 knockdown decreases mRNA m5C, reduces SRSF2 binding, and alters RNA splicing. The SRSF2P95H leukemia mutation impairs m5C binding and reduces SRSF2 association with key leukemia-related transcripts.","method":"m5C-RIP, structural analysis, mutagenesis of m5C-recognition residues, NSUN2 knockdown with RNA-seq, CLIP-seq","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — structural identification of binding residues plus mutagenesis plus functional splicing and binding assays, multiple orthogonal methods","pmids":["38065062"],"is_preprint":false},{"year":2024,"finding":"SRSF2P95H mutation disrupts splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. A mitochondrial surveillance mechanism was identified whereby mitochondrial dysfunction modifies splicing of PINK1 to remove a poison intron, increasing PINK1 mRNA/protein stability and abundance; this increased PINK1-mediated mitophagy is essential for survival of SRSF2P95H/+ cells.","method":"RNA-seq for mitochondrial mRNA splicing, mitochondrial complex activity assays, PINK1 splicing reporter, GSK-3 inhibitor treatment, apoptosis assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (mitochondrial function, splicing reporters, pharmacologic intervention) in isogenic mutant cells","pmids":["38713535"],"is_preprint":false},{"year":2009,"finding":"TBX5 associates with SC35 (shown by co-immunoprecipitation and GST pulldown) and competes with SC35 for binding to 5' splice site RNA; co-expression of TBX5 and SC35 antagonizes each other's positive effect on splicing. The severe TBX5 G80R mutation (full cardiac penetrance) strongly affects splicing, linking SC35 interaction to Holt-Oram syndrome pathogenesis.","method":"Co-immunoprecipitation, GST pulldown, RNA homopolymer binding assay, minigene splicing assay, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus pulldown plus functional splicing assay, single lab","pmids":["19648116"],"is_preprint":false},{"year":2008,"finding":"SC35 (acting through its RRM domain) and ASF/SF2 act antagonistically to regulate growth hormone exon 3 splicing; SC35 acts as a repressor via a site downstream of ESE2, and a patient mutation that creates a functional SC35-binding site causes pathological exon 3 skipping.","method":"Chimeric SC35/ASF-SF2 domain swaps, minigene splicing assay, patient mutation analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-swap mutagenesis plus minigene splicing assay with patient mutation, single lab","pmids":["18586677"],"is_preprint":false},{"year":2005,"finding":"SC35 promotes a shift from primary AChE-S to stress-induced AChE-R splice variant in cotransfection assays, with this activity mapping to the SC35 RRM domain (via chimeric SC35/ASF-SF2 constructs); SC35 levels are elevated in stressed mouse prefrontal cortex coinciding with increased AChE-R mRNA.","method":"AChE minigene cotransfection, chimeric RRM/RS domain constructs, RT-PCR, in vivo stress model","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapping with chimeric constructs plus in vivo correlation, single lab","pmids":["16116489"],"is_preprint":false},{"year":2022,"finding":"SRSF2 is essential for myogenesis: conditional knockout in Myf5-lineage cells causes complete absence of mature myofibers and neonatal death; SRSF2-null Myf5-derived cells are scattered outside myogenic regions, fail to adopt myogenic fate (shown by lineage tracing), and undergo apoptosis.","method":"Conditional knockout (Myf5-Cre), lineage tracing, single-cell RNA-seq, apoptosis assays","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with lineage tracing and single-cell RNA-seq, defined cellular phenotype","pmids":["35460187"],"is_preprint":false}],"current_model":"SRSF2 (SC35) is an SR family splicing factor that binds pre-mRNA at degenerate SSNG (C/G-containing) ESE motifs through its RRM domain—whose L3 loop and m5C-reading residues are critical for binding—to promote spliceosome assembly and exon inclusion; it also affects transcriptional elongation by facilitating P-TEFb/CDK9 recruitment and CTD Ser2 phosphorylation, autoregulates its own mRNA levels via NMD-coupled alternative splicing, and is subject to post-translational control by Tip60-mediated K52 acetylation (promoting proteasomal degradation) and SRPK1/2-mediated RS-domain phosphorylation; oncogenic missense mutations at Pro95 shift its RNA binding specificity (UCCAG vs. UGGAG preference), impairing m5C reading, enhancing EJC-dependent NMD, disrupting mitochondrial mRNA splicing and PINK1-mediated mitophagy surveillance, and globally mis-splicing hematopoietic regulators to drive myelodysplastic/myeloproliferative neoplasms."},"narrative":{"mechanistic_narrative":"SRSF2 (SC35) is an essential SR-family pre-mRNA splicing factor that recognizes degenerate exonic splicing enhancers through its RRM and promotes spliceosome assembly, splice-site selection, and exon inclusion across many tissue-specific programs [PMID:1373910, PMID:1454802]. It was originally isolated as a factor required for the first step of splicing and for spliceosome assembly, reconstituting splicing activity in S100 and immunodepleted extracts where it favors proximal splice sites in antagonism with hnRNP A1 [PMID:1373910, PMID:1454802], and it can substitute for U2AF65 to recruit U2 snRNP in a substrate-specific, U1 snRNP-dependent manner [PMID:8990173]. Sequence-specificity studies and solution NMR structures of the RRM define a high-affinity 5'-SSNG-3' consensus, with the protein binding 5'-UCCAGU-3' and 5'-UGGAGU-3' equally by flipping central C or G bases between anti and syn conformations and with the elongated L3 loop essential for RNA contact [PMID:10629063, PMID:22002536, PMID:22140111]; the RRM also serves as a reader of m5C-modified mRNA, with NSUN2-deposited m5C enhancing SRSF2 binding [PMID:38065062]. Beyond splicing, SRSF2 facilitates transcriptional elongation by promoting P-TEFb recruitment and CTD Ser2 phosphorylation [PMID:18641664] and autoregulates its own expression through alternative splicing of its terminal exon coupled to mRNA surveillance [PMID:11285241, PMID:19965769]. Its activity is tuned by post-translational control, including Tip60-mediated K52 acetylation that drives proteasomal degradation and HDAC6/SRPK opposition [PMID:21157427]. Genetically, SRSF2 is required for T cell maturation, cardiac and hepatic homeostasis, and myogenesis, regulating defined targets such as CD45, RyR2, and stress-death pathway genes [PMID:11239462, PMID:14963485, PMID:27022105, PMID:35460187]. Recurrent Pro95 hot-spot mutations (e.g., P95H) cause myelodysplastic/myeloproliferative neoplasms by shifting RNA-binding specificity toward UCCAG over UGGAG motifs, mis-splicing hematopoietic regulators including EZH2 and HNRNPA2B1, enhancing EJC-dependent nonsense-mediated decay, impairing m5C reading, and disrupting mitochondrial mRNA splicing such that PINK1-mediated mitophagy becomes essential for mutant-cell survival [PMID:25965569, PMID:26261309, PMID:29858584, PMID:32001512, PMID:38065062, PMID:38713535].","teleology":[{"year":1992,"claim":"Established SRSF2's foundational identity by showing it is a splicing factor required for the first catalytic step and spliceosome assembly, defining it as an SR-family protein.","evidence":"cDNA cloning and in vitro splicing reconstitution revealing an RNP RNA-binding motif and a C-terminal SR domain; recombinant protein reconstitutes splicing and favors proximal splice sites antagonized by hnRNP A1","pmids":["1373910","1454802"],"confidence":"High","gaps":["RNA sequence specificity not yet defined","Mechanism of splice-site proximity bias not resolved structurally"]},{"year":1997,"claim":"Showed SRSF2 can recruit U2 snRNP independently of U2AF65, revealing an alternative pathway for early spliceosome assembly.","evidence":"U2AF affinity depletion from HeLa extracts and reconstitution with recombinant SC35","pmids":["8990173"],"confidence":"High","gaps":["Substrate determinants of U2AF-independence unknown","Generality across pre-mRNAs untested"]},{"year":2000,"claim":"Defined SRSF2's distinct functional RNA specificity, separating it from SF2/ASF and establishing it recognizes a dedicated ESE class.","evidence":"In vitro functional SELEX under splicing conditions with S100/nuclear-extract complementation","pmids":["7543047","10629063"],"confidence":"High","gaps":["Structural basis of specificity not yet known","Relationship to in vivo binding sites unresolved"]},{"year":2001,"claim":"Revealed SRSF2 autoregulates its abundance, defining a feedback circuit coupling its own splicing to mRNA surveillance.","evidence":"Overexpression, in vitro splicing, siRNA knockdown and mRNA stability assays in HeLa; effect specific to SC35","pmids":["11285241"],"confidence":"High","gaps":["Trans-factors antagonizing autoregulation not fully mapped at this stage"]},{"year":2001,"claim":"Demonstrated SRSF2 is a physiological splicing regulator in vivo, controlling tissue-specific programs and cell maturation.","evidence":"Conditional KO in thymus with CD45 isoform RT-PCR; later conditional KOs in heart (RyR2), MEFs (p53/SirT1 pathway), liver, and muscle","pmids":["11239462","14963485","17526736","35460187"],"confidence":"High","gaps":["Whether phenotypes reflect splicing vs transcriptional elongation roles not always separated","Full target spectrum per tissue incomplete"]},{"year":2008,"claim":"Linked SRSF2 to transcriptional elongation, establishing a role beyond splicing in coupling RNA Pol II activity to processing.","evidence":"siRNA depletion with Pol II/P-TEFb ChIP and recombinant-SC35-rescued nuclear run-on showing CTD Ser2 phosphorylation control","pmids":["18641664"],"confidence":"High","gaps":["Direct interaction with P-TEFb not biochemically defined","Mechanism of CTD kinase recruitment unresolved"]},{"year":2010,"claim":"Defined post-translational control of SRSF2 abundance and activity, showing acetylation/phosphorylation balance governs splicing-dependent cell fate.","evidence":"In vitro acetylation, K52 mutagenesis, Co-IP and knockdown showing Tip60 acetylation drives degradation while HDAC6 stabilizes; SRPK nuclear translocation regulation; caspase-8 splicing readout","pmids":["21157427"],"confidence":"High","gaps":["Stoichiometry of acetylation in vivo unknown","Interplay with phosphorylation site occupancy not quantified"]},{"year":2011,"claim":"Provided the structural basis for SRSF2 RNA recognition, explaining its degenerate SSNG specificity through base-flipping and an atypical L3 loop.","evidence":"Solution NMR structures of free and RNA-bound RRM with mutagenesis, ITC, and functional splicing validation","pmids":["22002536","22140111"],"confidence":"High","gaps":["Structure of full-length protein with RS domain not determined","Basis for in vivo site selection beyond consensus unresolved"]},{"year":2015,"claim":"Established that Pro95 hot-spot mutations are change-of-function alleles that reprogram RNA-binding specificity to drive myeloid neoplasia.","evidence":"Conditional knockin mice, CRISPR isogenic K562 cells, RNA gel shifts and RNA-seq showing UCCAG-favoring/UGGAG-disfavoring shift, EZH2 mis-splicing/NMD, and hematopoietic differentiation defects","pmids":["25965569","26261309","26124281"],"confidence":"High","gaps":["Full set of disease-driving targets not defined","Why HSC context is required for transformation unexplained at this stage"]},{"year":2018,"claim":"Refined the mutant mechanism by showing much mis-splicing is indirect, propagating through mis-regulation of other RNA-processing factors.","evidence":"HITS-CLIP and RNA-seq in mutant cells with in vivo differentiation assay implicating HNRNPA2B1 mis-splicing; physiological knockin MDS/MPN model","pmids":["29858584","29903888"],"confidence":"High","gaps":["Hierarchy of direct vs cascade targets incompletely ordered","Contribution of each downstream factor not quantified"]},{"year":2020,"claim":"Connected mutant SRSF2 to enhanced nonsense-mediated decay through EJC deposition, defining a degradation arm of its oncogenic program.","evidence":"RNA-seq, EJC deposition assays, and antisense-oligonucleotide rescue in isogenic mutant cells","pmids":["32001512"],"confidence":"High","gaps":["Generality of EJC-coupled decay across mutant targets unresolved","Therapeutic window of ASO rescue untested clinically"]},{"year":2023,"claim":"Identified SRSF2 as an m5C reader, adding an RNA-modification-dependent layer to its binding and explaining a further defect of the P95H mutant.","evidence":"m5C-RIP, structural identification of recognition residues with mutagenesis, NSUN2 knockdown with RNA-seq and CLIP-seq","pmids":["38065062"],"confidence":"High","gaps":["Genome-wide overlap of m5C reading with classical ESE binding unresolved","Contribution of m5C reading to disease phenotype not quantified"]},{"year":2024,"claim":"Revealed a mitochondrial vulnerability of mutant cells, showing PINK1-mediated mitophagy becomes essential when SRSF2 P95H disrupts mitochondrial mRNA splicing.","evidence":"RNA-seq of mitochondrial mRNA splicing, complex I activity assays, PINK1 splicing reporter, GSK-3 inhibitor and apoptosis assays in isogenic mutant cells","pmids":["38713535"],"confidence":"High","gaps":["Whether mitophagy dependency is therapeutically exploitable untested in vivo","Mechanism coupling mitochondrial dysfunction to PINK1 intron removal incompletely defined"]},{"year":null,"claim":"How SRSF2's splicing, transcriptional elongation, m5C-reading, and autoregulatory activities are integrated and differentially deployed across normal tissues versus mutant disease states remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling direct vs cascade targets in disease","Structure of full-length protein in complex with spliceosome unknown","Tissue-specific determinants of target selection undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2,4,16,17,30]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[11,24]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,1,3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,11]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,16]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[11,24]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[20,25,26,31]}],"complexes":[],"partners":["TBX5","SFPQ","NONO","EP300","DYRK1A","KAT5","SRPK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q01130","full_name":"Serine/arginine-rich splicing factor 2","aliases":["Protein PR264","Splicing component, 35 kDa","Splicing factor SC35","SC-35","Splicing factor, arginine/serine-rich 2"],"length_aa":221,"mass_kda":25.5,"function":"Necessary for the splicing of pre-mRNA. 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(Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/21555914","citation_count":27,"is_preprint":false},{"pmid":"18586677","id":"PMC_18586677","title":"Growth hormone deficiency and splicing fidelity: two serine/arginine-rich proteins, ASF/SF2 and SC35, act antagonistically.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18586677","citation_count":26,"is_preprint":false},{"pmid":"11101696","id":"PMC_11101696","title":"Uterine expression of alternatively spliced mRNAs of mouse splicing factor SC35 during early pregnancy.","date":"2000","source":"Molecular human reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/11101696","citation_count":25,"is_preprint":false},{"pmid":"26534959","id":"PMC_26534959","title":"HIV-1-Tat Protein Inhibits SC35-mediated Tau Exon 10 Inclusion through Up-regulation of DYRK1A Kinase.","date":"2015","source":"The Journal of biological 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pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"SC35 (SRSF2) was isolated as a splicing factor required for the first step of the splicing reaction and for spliceosome assembly; its cDNA revealed it contains an RNP-type RNA binding motif and a C-terminal SR domain, making it a member of the SR protein family.\",\n      \"method\": \"cDNA cloning, in vitro splicing reconstitution assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical reconstitution of splicing activity, foundational cloning paper replicated by multiple subsequent studies\",\n      \"pmids\": [\"1373910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Recombinant SC35 can reconstitute splicing activity in S100 extracts and in SC35-immunodepleted nuclear extracts; SC35 favors proximal 5' and 3' splice sites, an effect antagonized by hnRNP A1.\",\n      \"method\": \"In vitro splicing reconstitution assay with recombinant proteins and immunodepleted extracts\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with recombinant proteins, replicated across labs\",\n      \"pmids\": [\"1454802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"SC35 and ASF/SF2 have distinct, functionally significant RNA binding specificities determined by SELEX; the arginine-serine region is not the major determinant of specificity. Unlike ASF/SF2, a SC35 high-affinity binding site element did not function as a splicing enhancer in S100 complementation assays.\",\n      \"method\": \"SELEX, RNA binding assays, in vitro splicing complementation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — SELEX plus functional splicing assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"7543047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"SC35 can functionally substitute for U2AF65 in reconstituting pre-mRNA splicing in U2AF-depleted HeLa nuclear extracts, in a substrate-specific and U1 snRNP-dependent manner, demonstrating a U2AF-independent pathway for U2 snRNP recruitment.\",\n      \"method\": \"Affinity depletion of U2AF from nuclear extracts, in vitro splicing reconstitution with recombinant SC35\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with depleted extracts and recombinant protein, clean mechanistic demonstration\",\n      \"pmids\": [\"8990173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"A novel ESE motif recognized by SC35 under splicing conditions was identified by in vitro functional SELEX; SC35-selected sequences promote splicing in nuclear extract or S100 complemented by SC35 but not by SF2/ASF, demonstrating distinct and functional RNA sequence specificity.\",\n      \"method\": \"In vitro SELEX under splicing conditions, in vitro splicing assays in S100 and nuclear extracts\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — SELEX plus functional splicing validation with multiple substrates and controls\",\n      \"pmids\": [\"10629063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SC35 autoregulates its own expression by activating specific alternative splicing events in the 3' UTR of its own pre-mRNA, producing unstable mRNA isoforms subject to mRNA surveillance; this effect is specific to SC35 and not shared by ASF/SF2 or 9G8.\",\n      \"method\": \"Overexpression in HeLa cells, in vitro splicing with recombinant SR proteins, siRNA knockdown, mRNA stability assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro splicing reconstitution plus in vivo overexpression and stability assays, specific to SC35\",\n      \"pmids\": [\"11285241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Cre-mediated conditional deletion of SC35 in the thymus causes a defect in T cell maturation and alters alternative splicing of CD45 (a receptor tyrosine phosphatase), establishing SC35 as a physiological regulator of a T cell-specific splicing pathway.\",\n      \"method\": \"Conditional knockout mouse (Cre-lox), RT-PCR for CD45 isoforms\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with defined molecular phenotype (CD45 splicing), replicated in vivo\",\n      \"pmids\": [\"11239462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"GSK-3 phosphorylates SC35 in vitro (on a peptide from its SR domain requiring priming phosphorylation) and affects its intranuclear distribution; GSK-3 inhibition in neurons redistributes SC35 to nuclear speckles and increases tau exon 10 inclusion.\",\n      \"method\": \"In vitro kinase assay with recombinant GSK-3β, immunoprecipitation of SC35, immunofluorescence, RT-PCR for tau splicing\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay plus cell-based splicing change, single lab\",\n      \"pmids\": [\"14602710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Tissue-specific ablation of SC35 in the heart causes dilated cardiomyopathy preceded by downregulation of cardiac ryanodine receptor 2 (RyR2), with mutant cardiomyocytes showing frequency-dependent excitation-contraction coupling defects.\",\n      \"method\": \"Conditional knockout mouse (MLC-2v-Cre), microarray, RT-PCR, calcium imaging\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with specific molecular target (RyR2 downregulation) and functional readout\",\n      \"pmids\": [\"14963485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SC35 is responsible for aberrant splicing of E1alpha pyruvate dehydrogenase mRNA caused by a disease mutation: the mutation increases SC35 binding to a cryptic splice donor, and siRNA-mediated reduction of SC35 in patient fibroblasts abolishes the aberrant splice product.\",\n      \"method\": \"RNA binding assays, overexpression, siRNA knockdown in patient fibroblasts, RT-PCR\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA rescue in patient cells plus binding assay, multiple orthogonal methods\",\n      \"pmids\": [\"15798212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Loss of SC35 in mouse embryonic fibroblasts induces G2/M cell cycle arrest and genomic instability via p53 hyperphosphorylation (linked to ATM activation) and hyperacetylation (attributed to increased p300 expression and aberrant SirT1 splicing); SC35 also controls cell proliferation during pituitary gland development but is dispensable in mature cardiomyocytes.\",\n      \"method\": \"Conditional knockout mouse, cell cycle analysis, immunoblotting for p53 modifications, RT-PCR for SirT1 splicing\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with mechanistic pathway placement via p53 modifications and specific splicing target\",\n      \"pmids\": [\"17526736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SC35 depletion induces RNA Pol II accumulation within gene bodies and attenuated transcriptional elongation, correlated with defective P-TEFb recruitment and dramatically reduced CTD Ser2 phosphorylation; recombinant SC35 rescues this elongation defect in nuclear run-on experiments.\",\n      \"method\": \"siRNA depletion, ChIP for Pol II and P-TEFb, nuclear run-on assay with recombinant SC35\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — recombinant protein rescue in nuclear run-on plus ChIP, multiple orthogonal methods\",\n      \"pmids\": [\"18641664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"E2F1 transcriptionally upregulates SC35 (SRSF2) expression; SC35 is required for E2F1-induced switching of alternative splicing of apoptotic genes (c-FLIP, caspase-8, caspase-9, Bcl-x) toward pro-apoptotic splice variants and for apoptosis in response to DNA-damaging agents.\",\n      \"method\": \"ChIP for E2F1 at SRSF2 promoter, siRNA knockdown of SC35, RT-PCR for splice isoforms, apoptosis assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP plus siRNA with defined splicing readouts, multiple targets validated\",\n      \"pmids\": [\"18806759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SC35 promotes tau exon 10 inclusion by binding to a SC35-like exonic splicing enhancer on tau pre-mRNA; mutation of this element abolishes both SC35 binding and exon inclusion. Dyrk1A phosphorylates SC35 in vitro and interacts with SC35 in cells, and overexpression of Dyrk1A suppresses SC35's ability to promote tau exon 10 inclusion.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, minigene splicing assay, mutation analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay plus RIP plus minigene mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"21470964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The SC35 terminal intron self-regulation involves exonic splicing enhancer elements in the last exon that respond specifically to SC35; hnRNP H and TDP-43 antagonize SC35 binding to the terminal exon and repress SC35 terminal 3' splice site usage.\",\n      \"method\": \"Minigene splicing assays, RNA binding competition assays, in vitro and in cellulo splicing\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and cell-based splicing assays, single lab with multiple constructs\",\n      \"pmids\": [\"19965769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Tip60 acetyltransferase acetylates SRSF2 on lysine 52 (within the RRM), promoting its proteasomal degradation; HDAC6 deacetylase counters this acetylation and acts as a positive regulator of SRSF2 protein level. Tip60 also downregulates SRSF2 phosphorylation by inhibiting nuclear translocation of SRPK1 and SRPK2. This acetylation/phosphorylation network controls caspase-8 pre-mRNA splicing and cell fate in response to cisplatin.\",\n      \"method\": \"In vitro acetylation assay, site-directed mutagenesis (K52), co-immunoprecipitation, siRNA knockdown, RT-PCR for caspase-8 isoforms\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro acetylation with mutagenesis plus functional splicing readout, multiple orthogonal methods\",\n      \"pmids\": [\"21157427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The solution NMR structure of SRSF2 RRM bound to 5'-UCCAGU-3' and 5'-UGGAGU-3' RNA reveals a sandwich-like structure; SRSF2 binds both sequences equally by flipping the two central C or G bases into anti or syn conformation. The L3 loop is crucial for RNA binding (NMR/mutagenesis). The high-affinity consensus is 5'-SSNG-3' (S=C/G), validated by in vitro and in vivo splicing assays.\",\n      \"method\": \"NMR structure determination, mutagenesis, ITC/binding assays, in vitro and in vivo splicing assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure plus mutagenesis plus functional validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"22002536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The solution structure of the free SRSF2 RRM (residues 9-101) was determined; unlike other SR proteins, SRSF2 has a longer L3 loop and lacks the conserved aromatic residue in RNP2. The L3 loop (in addition to canonical β1/β3 strands) is essential for RNA binding, shown by NMR chemical shift perturbation and mutagenesis; RNA 5'-AGCAGAGUA-3' binds with Kd = 61 nM.\",\n      \"method\": \"NMR structure determination, ITC, site-directed mutagenesis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure plus mutagenesis plus quantitative binding measurement\",\n      \"pmids\": [\"22140111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SC35 binds tau exon 10 mRNA via the SC35-like element and stabilizes tau mRNA (specifically exon 10-containing isoforms) without affecting tau transcription, thereby promoting tau protein expression.\",\n      \"method\": \"RNA immunoprecipitation (RIP), mRNA stability assay, RT-PCR, overexpression\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RIP plus mRNA stability assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"21333649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SRSF2 promotes splicing and transcription of exon 11-included isoform of the Ron proto-oncogene by binding to a CGAG sequence on exon 11; mutation of this sequence abolishes both physical interaction and splicing promotion.\",\n      \"method\": \"Knockdown/overexpression, RT-PCR, RNA pull-down/mutation analysis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — mutagenesis of binding site with functional readout, single lab\",\n      \"pmids\": [\"25220236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SRSF2 mutations (e.g., P95H) alter SRSF2's sequence-specific RNA binding activity, changing recognition of specific ESE motifs to drive recurrent mis-splicing of hematopoietic regulators including EZH2 (triggering NMD), thereby impairing hematopoietic differentiation in vivo.\",\n      \"method\": \"Conditional knockin mouse, RNA-seq, in vivo differentiation assays, splicing reporter assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockin mouse model with RNA-seq and functional hematopoietic phenotype, independently replicated\",\n      \"pmids\": [\"25965569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SRSF2 P95H mutation introduced by CRISPR into K562 cells alters RNA binding affinity in a motif-specific manner: mutant SRSF2 binds UCCAG sites more tightly and UGGAG sites less tightly than wild-type, causing corresponding increased or decreased exon inclusion; protein-protein interactions with key splicing factors are unaffected by the mutation.\",\n      \"method\": \"CRISPR knockin, RNA gel shift assays, RNA-seq for splicing changes, co-immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — isogenic CRISPR model plus in vitro RNA binding assays with mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"26261309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Ablation of SRSF2 in the hematopoietic lineage causes embryonic lethality with enhanced apoptosis and decreased hematopoietic stem/progenitor cells; adult conditional knockout shows decreased LSK cells; MDS-associated P95H and P95-R102 deletion mutations cause significant changes in alternative splicing of genes enriched in cancer and apoptosis.\",\n      \"method\": \"Conditional knockout mouse (Mx1-Cre), RNA-seq for splicing changes, HSPC flow cytometry\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with defined cellular and molecular phenotypes, multiple splice targets identified\",\n      \"pmids\": [\"26124281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SRSF2 binding within an alternative exon is associated with its inclusion, whereas SRSF2 binding in a flanking constitutive exon is associated with exclusion of the alternative exon; SRSF2 regulates alternative splicing driving hepatocellular carcinoma progression.\",\n      \"method\": \"CLIP-seq/RNA-seq, knockdown/overexpression, RT-PCR for splice isoforms\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CLIP-seq binding mapped to splicing outcomes, single lab\",\n      \"pmids\": [\"28082404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Liver-specific deletion of SRSF2 (but not SRSF1) causes acute liver failure; SRSF2 governs splicing of multiple stress-induced cell death pathway genes and acts as a transcription activator required for expression of transcription factors controlling energy homeostasis and bile acid metabolism.\",\n      \"method\": \"Liver-specific conditional knockout mouse (Cre-lox), RNA-seq, histology, biochemical assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO with global RNA-seq and defined metabolic/splicing phenotypes\",\n      \"pmids\": [\"27022105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SRSF2P95H mutation globally alters RNA binding (HITS-CLIP) and splicing; most differential binding events do not directly translate to local exon splicing changes, suggesting indirect/cascade effects. SRSF2P95H targets are enriched in RNA processing genes including hnRNP and SR family members; aberrant splicing of HNRNPA2B1 was shown to impair hematopoietic differentiation in vivo.\",\n      \"method\": \"HITS-CLIP, RNA-seq, in vivo hematopoietic differentiation assay\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — HITS-CLIP plus RNA-seq plus in vivo functional validation, multiple orthogonal methods\",\n      \"pmids\": [\"29858584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Conditional knockin mice expressing Srsf2 P95H heterozygously from endogenous locus develop progressive transplantable MDS/MPN with myeloid bias, monocytosis, and dysplasia during native hematopoiesis (no transplant stress); the mutation must occur in HSC-containing populations to promote disease.\",\n      \"method\": \"Conditional knockin mouse (multiple Cre lines), transplantation assay, RNA-seq\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — physiological knockin model with defined HSC phenotype and RNA splicing changes, replicated across Cre lines\",\n      \"pmids\": [\"29903888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SRSF2 associates with the P300/CBP acetyltransferase complex and alters H3K27Ac levels near immune checkpoint gene transcription start sites, thereby influencing STAT3 recruitment to these promoters and regulating transcription of multiple immune checkpoint molecules (PD-1, TIM-3, etc.) in exhausted T cells.\",\n      \"method\": \"Co-immunoprecipitation, ChIP for H3K27Ac and STAT3, siRNA knockdown, RT-PCR\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus ChIP plus functional knockdown, single lab\",\n      \"pmids\": [\"31838573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SRSF2 Pro95 hot-spot mutations enhance mRNA decay (NMD) through sequence-specific RNA binding and splicing; mutant SRSF2 enhances deposition of exon junction complexes (EJCs) downstream from PTCs via RNA-mediated molecular interactions, recruiting NMD factors. Antisense oligonucleotide blocking of EJC deposition restores PTC-containing transcript levels.\",\n      \"method\": \"RNA-seq, EJC deposition assays, antisense oligonucleotide rescue, splicing reporter assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple mechanistic assays (EJC deposition, ASO rescue, splicing) with isogenic mutant cells\",\n      \"pmids\": [\"32001512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SFPQ, in complex with p54nrb, binds SRSF2 under platinum treatment and decreases SRSF2 binding to caspase-9 RNA, favoring expression of its antiapoptotic alternatively spliced form and contributing to chemoresistance.\",\n      \"method\": \"Co-immunoprecipitation (SFPQ/p54nrb/SRSF2 complex), RNA immunoprecipitation for caspase-9, siRNA knockdown, RT-PCR for splice isoforms\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal Co-IP plus RIP with functional splicing readout, single lab\",\n      \"pmids\": [\"32332923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SRSF2 functions as a reader of m5C RNA modification; structurally identified residues mediate m5C recognition. NSUN2 knockdown decreases mRNA m5C, reduces SRSF2 binding, and alters RNA splicing. The SRSF2P95H leukemia mutation impairs m5C binding and reduces SRSF2 association with key leukemia-related transcripts.\",\n      \"method\": \"m5C-RIP, structural analysis, mutagenesis of m5C-recognition residues, NSUN2 knockdown with RNA-seq, CLIP-seq\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — structural identification of binding residues plus mutagenesis plus functional splicing and binding assays, multiple orthogonal methods\",\n      \"pmids\": [\"38065062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SRSF2P95H mutation disrupts splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. A mitochondrial surveillance mechanism was identified whereby mitochondrial dysfunction modifies splicing of PINK1 to remove a poison intron, increasing PINK1 mRNA/protein stability and abundance; this increased PINK1-mediated mitophagy is essential for survival of SRSF2P95H/+ cells.\",\n      \"method\": \"RNA-seq for mitochondrial mRNA splicing, mitochondrial complex activity assays, PINK1 splicing reporter, GSK-3 inhibitor treatment, apoptosis assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (mitochondrial function, splicing reporters, pharmacologic intervention) in isogenic mutant cells\",\n      \"pmids\": [\"38713535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TBX5 associates with SC35 (shown by co-immunoprecipitation and GST pulldown) and competes with SC35 for binding to 5' splice site RNA; co-expression of TBX5 and SC35 antagonizes each other's positive effect on splicing. The severe TBX5 G80R mutation (full cardiac penetrance) strongly affects splicing, linking SC35 interaction to Holt-Oram syndrome pathogenesis.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, RNA homopolymer binding assay, minigene splicing assay, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus pulldown plus functional splicing assay, single lab\",\n      \"pmids\": [\"19648116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SC35 (acting through its RRM domain) and ASF/SF2 act antagonistically to regulate growth hormone exon 3 splicing; SC35 acts as a repressor via a site downstream of ESE2, and a patient mutation that creates a functional SC35-binding site causes pathological exon 3 skipping.\",\n      \"method\": \"Chimeric SC35/ASF-SF2 domain swaps, minigene splicing assay, patient mutation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-swap mutagenesis plus minigene splicing assay with patient mutation, single lab\",\n      \"pmids\": [\"18586677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SC35 promotes a shift from primary AChE-S to stress-induced AChE-R splice variant in cotransfection assays, with this activity mapping to the SC35 RRM domain (via chimeric SC35/ASF-SF2 constructs); SC35 levels are elevated in stressed mouse prefrontal cortex coinciding with increased AChE-R mRNA.\",\n      \"method\": \"AChE minigene cotransfection, chimeric RRM/RS domain constructs, RT-PCR, in vivo stress model\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping with chimeric constructs plus in vivo correlation, single lab\",\n      \"pmids\": [\"16116489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SRSF2 is essential for myogenesis: conditional knockout in Myf5-lineage cells causes complete absence of mature myofibers and neonatal death; SRSF2-null Myf5-derived cells are scattered outside myogenic regions, fail to adopt myogenic fate (shown by lineage tracing), and undergo apoptosis.\",\n      \"method\": \"Conditional knockout (Myf5-Cre), lineage tracing, single-cell RNA-seq, apoptosis assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with lineage tracing and single-cell RNA-seq, defined cellular phenotype\",\n      \"pmids\": [\"35460187\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SRSF2 (SC35) is an SR family splicing factor that binds pre-mRNA at degenerate SSNG (C/G-containing) ESE motifs through its RRM domain—whose L3 loop and m5C-reading residues are critical for binding—to promote spliceosome assembly and exon inclusion; it also affects transcriptional elongation by facilitating P-TEFb/CDK9 recruitment and CTD Ser2 phosphorylation, autoregulates its own mRNA levels via NMD-coupled alternative splicing, and is subject to post-translational control by Tip60-mediated K52 acetylation (promoting proteasomal degradation) and SRPK1/2-mediated RS-domain phosphorylation; oncogenic missense mutations at Pro95 shift its RNA binding specificity (UCCAG vs. UGGAG preference), impairing m5C reading, enhancing EJC-dependent NMD, disrupting mitochondrial mRNA splicing and PINK1-mediated mitophagy surveillance, and globally mis-splicing hematopoietic regulators to drive myelodysplastic/myeloproliferative neoplasms.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SRSF2 (SC35) is an essential SR-family pre-mRNA splicing factor that recognizes degenerate exonic splicing enhancers through its RRM and promotes spliceosome assembly, splice-site selection, and exon inclusion across many tissue-specific programs [#0, #1]. It was originally isolated as a factor required for the first step of splicing and for spliceosome assembly, reconstituting splicing activity in S100 and immunodepleted extracts where it favors proximal splice sites in antagonism with hnRNP A1 [#0, #1], and it can substitute for U2AF65 to recruit U2 snRNP in a substrate-specific, U1 snRNP-dependent manner [#3]. Sequence-specificity studies and solution NMR structures of the RRM define a high-affinity 5'-SSNG-3' consensus, with the protein binding 5'-UCCAGU-3' and 5'-UGGAGU-3' equally by flipping central C or G bases between anti and syn conformations and with the elongated L3 loop essential for RNA contact [#4, #16, #17]; the RRM also serves as a reader of m5C-modified mRNA, with NSUN2-deposited m5C enhancing SRSF2 binding [#30]. Beyond splicing, SRSF2 facilitates transcriptional elongation by promoting P-TEFb recruitment and CTD Ser2 phosphorylation [#11] and autoregulates its own expression through alternative splicing of its terminal exon coupled to mRNA surveillance [#5, #14]. Its activity is tuned by post-translational control, including Tip60-mediated K52 acetylation that drives proteasomal degradation and HDAC6/SRPK opposition [#15]. Genetically, SRSF2 is required for T cell maturation, cardiac and hepatic homeostasis, and myogenesis, regulating defined targets such as CD45, RyR2, and stress-death pathway genes [#6, #8, #24, #35]. Recurrent Pro95 hot-spot mutations (e.g., P95H) cause myelodysplastic/myeloproliferative neoplasms by shifting RNA-binding specificity toward UCCAG over UGGAG motifs, mis-splicing hematopoietic regulators including EZH2 and HNRNPA2B1, enhancing EJC-dependent nonsense-mediated decay, impairing m5C reading, and disrupting mitochondrial mRNA splicing such that PINK1-mediated mitophagy becomes essential for mutant-cell survival [#20, #21, #25, #28, #30, #31].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established SRSF2's foundational identity by showing it is a splicing factor required for the first catalytic step and spliceosome assembly, defining it as an SR-family protein.\",\n      \"evidence\": \"cDNA cloning and in vitro splicing reconstitution revealing an RNP RNA-binding motif and a C-terminal SR domain; recombinant protein reconstitutes splicing and favors proximal splice sites antagonized by hnRNP A1\",\n      \"pmids\": [\"1373910\", \"1454802\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA sequence specificity not yet defined\", \"Mechanism of splice-site proximity bias not resolved structurally\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed SRSF2 can recruit U2 snRNP independently of U2AF65, revealing an alternative pathway for early spliceosome assembly.\",\n      \"evidence\": \"U2AF affinity depletion from HeLa extracts and reconstitution with recombinant SC35\",\n      \"pmids\": [\"8990173\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate determinants of U2AF-independence unknown\", \"Generality across pre-mRNAs untested\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined SRSF2's distinct functional RNA specificity, separating it from SF2/ASF and establishing it recognizes a dedicated ESE class.\",\n      \"evidence\": \"In vitro functional SELEX under splicing conditions with S100/nuclear-extract complementation\",\n      \"pmids\": [\"7543047\", \"10629063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of specificity not yet known\", \"Relationship to in vivo binding sites unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Revealed SRSF2 autoregulates its abundance, defining a feedback circuit coupling its own splicing to mRNA surveillance.\",\n      \"evidence\": \"Overexpression, in vitro splicing, siRNA knockdown and mRNA stability assays in HeLa; effect specific to SC35\",\n      \"pmids\": [\"11285241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trans-factors antagonizing autoregulation not fully mapped at this stage\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated SRSF2 is a physiological splicing regulator in vivo, controlling tissue-specific programs and cell maturation.\",\n      \"evidence\": \"Conditional KO in thymus with CD45 isoform RT-PCR; later conditional KOs in heart (RyR2), MEFs (p53/SirT1 pathway), liver, and muscle\",\n      \"pmids\": [\"11239462\", \"14963485\", \"17526736\", \"35460187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether phenotypes reflect splicing vs transcriptional elongation roles not always separated\", \"Full target spectrum per tissue incomplete\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked SRSF2 to transcriptional elongation, establishing a role beyond splicing in coupling RNA Pol II activity to processing.\",\n      \"evidence\": \"siRNA depletion with Pol II/P-TEFb ChIP and recombinant-SC35-rescued nuclear run-on showing CTD Ser2 phosphorylation control\",\n      \"pmids\": [\"18641664\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct interaction with P-TEFb not biochemically defined\", \"Mechanism of CTD kinase recruitment unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined post-translational control of SRSF2 abundance and activity, showing acetylation/phosphorylation balance governs splicing-dependent cell fate.\",\n      \"evidence\": \"In vitro acetylation, K52 mutagenesis, Co-IP and knockdown showing Tip60 acetylation drives degradation while HDAC6 stabilizes; SRPK nuclear translocation regulation; caspase-8 splicing readout\",\n      \"pmids\": [\"21157427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of acetylation in vivo unknown\", \"Interplay with phosphorylation site occupancy not quantified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided the structural basis for SRSF2 RNA recognition, explaining its degenerate SSNG specificity through base-flipping and an atypical L3 loop.\",\n      \"evidence\": \"Solution NMR structures of free and RNA-bound RRM with mutagenesis, ITC, and functional splicing validation\",\n      \"pmids\": [\"22002536\", \"22140111\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length protein with RS domain not determined\", \"Basis for in vivo site selection beyond consensus unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that Pro95 hot-spot mutations are change-of-function alleles that reprogram RNA-binding specificity to drive myeloid neoplasia.\",\n      \"evidence\": \"Conditional knockin mice, CRISPR isogenic K562 cells, RNA gel shifts and RNA-seq showing UCCAG-favoring/UGGAG-disfavoring shift, EZH2 mis-splicing/NMD, and hematopoietic differentiation defects\",\n      \"pmids\": [\"25965569\", \"26261309\", \"26124281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of disease-driving targets not defined\", \"Why HSC context is required for transformation unexplained at this stage\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Refined the mutant mechanism by showing much mis-splicing is indirect, propagating through mis-regulation of other RNA-processing factors.\",\n      \"evidence\": \"HITS-CLIP and RNA-seq in mutant cells with in vivo differentiation assay implicating HNRNPA2B1 mis-splicing; physiological knockin MDS/MPN model\",\n      \"pmids\": [\"29858584\", \"29903888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy of direct vs cascade targets incompletely ordered\", \"Contribution of each downstream factor not quantified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected mutant SRSF2 to enhanced nonsense-mediated decay through EJC deposition, defining a degradation arm of its oncogenic program.\",\n      \"evidence\": \"RNA-seq, EJC deposition assays, and antisense-oligonucleotide rescue in isogenic mutant cells\",\n      \"pmids\": [\"32001512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of EJC-coupled decay across mutant targets unresolved\", \"Therapeutic window of ASO rescue untested clinically\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified SRSF2 as an m5C reader, adding an RNA-modification-dependent layer to its binding and explaining a further defect of the P95H mutant.\",\n      \"evidence\": \"m5C-RIP, structural identification of recognition residues with mutagenesis, NSUN2 knockdown with RNA-seq and CLIP-seq\",\n      \"pmids\": [\"38065062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide overlap of m5C reading with classical ESE binding unresolved\", \"Contribution of m5C reading to disease phenotype not quantified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a mitochondrial vulnerability of mutant cells, showing PINK1-mediated mitophagy becomes essential when SRSF2 P95H disrupts mitochondrial mRNA splicing.\",\n      \"evidence\": \"RNA-seq of mitochondrial mRNA splicing, complex I activity assays, PINK1 splicing reporter, GSK-3 inhibitor and apoptosis assays in isogenic mutant cells\",\n      \"pmids\": [\"38713535\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mitophagy dependency is therapeutically exploitable untested in vivo\", \"Mechanism coupling mitochondrial dysfunction to PINK1 intron removal incompletely defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SRSF2's splicing, transcriptional elongation, m5C-reading, and autoregulatory activities are integrated and differentially deployed across normal tissues versus mutant disease states remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling direct vs cascade targets in disease\", \"Structure of full-length protein in complex with spliceosome unknown\", \"Tissue-specific determinants of target selection undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2, 4, 16, 17, 30]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [11, 24]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 11]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 16]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [11, 24]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [20, 25, 26, 31]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TBX5\", \"SFPQ\", \"NONO\", \"EP300\", \"DYRK1A\", \"KAT5\", \"SRPK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}