{"gene":"SRSF3","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":2001,"finding":"SRp20 (SRSF3) interacts specifically with a 22-nt RNA element from the histone H2a gene to promote nucleocytoplasmic export of intronless mRNAs in mammalian cells and Xenopus oocytes. Antibodies to SRp20 eliminate RNA binding and inhibit export. SRp20 can be UV cross-linked to polyadenylated RNA in both nucleus and cytoplasm of HeLa cells.","method":"UV cross-linking, transient transfection, Xenopus oocyte microinjection, antibody inhibition","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (UV cross-linking, microinjection, antibody inhibition) replicated in two cell systems","pmids":["11336712"],"is_preprint":false},{"year":1997,"finding":"SRp20 regulates alternative splicing of its own pre-mRNA by enhancing recognition of the weak splice acceptor of exon 4, leading to exon 4 inclusion and production of a truncated protein lacking the RS domain. ASF/SF2 antagonizes this autoregulation by suppressing use of the exon 4 splice donor.","method":"Reporter gene constructs, overexpression, transfection assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple reporter constructs with defined splice site elements, replicated finding of autoregulation","pmids":["9305649"],"is_preprint":false},{"year":1999,"finding":"The RNA recognition motif (RRM) of SRp20 recognizes sequences similar to those selected by mutated zinc-knuckle 9G8, and SRp20 acts as an efficient splicing transactivator through its specific RNA targets. Recombinant SRp20 activates splicing in vitro of heterologous exons containing its binding sequences.","method":"SELEX, UV cross-linking, immunoprecipitation, S100 complementation with recombinant proteins","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified recombinant proteins, SELEX binding specificity, single lab","pmids":["10094314"],"is_preprint":false},{"year":1998,"finding":"SRp20 affects alternative 3'-terminal exon recognition in the calcitonin/CGRP gene via enhancing CstF binding to the alternative polyadenylation site. Wild-type SRp20 enhances exon 4 inclusion, while a mutant lacking the RS domain inhibits exon 4 inclusion by inhibiting CstF binding to the poly(A) site.","method":"Transfection with wild-type and mutant SRp20, polyadenylation factor binding assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain-mapping mutagenesis combined with binding assays, two functional variants tested","pmids":["9710581"],"is_preprint":false},{"year":2006,"finding":"The C-terminal domain (CTD) of RNA polymerase II is required for the inhibitory action of SRp20 on inclusion of a fibronectin cassette exon. The CTD promotes exon skipping by recruiting SRp20 in a manner that is independent of effects on transcription elongation rate.","method":"Alpha-amanitin-resistant pol II CTD mutants, fibronectin reporter minigenes","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic CTD mutants combined with reporter minigenes, mechanistic dissection of elongation-independent effect","pmids":["17028590"],"is_preprint":false},{"year":2006,"finding":"SRp20 and 9G8 contain a short arginine-rich peptide adjacent to their RRMs that does not contact RNA but is necessary and sufficient for interaction with the mRNA export factor TAP/NXF1. NMR solution structure of SRp20 RRM in complex with 5'CAUC3' RNA revealed that all 4 nt are contacted but only the 5' cytosine is specifically recognized.","method":"NMR solution structure, binding assays, peptide mutagenesis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with functional validation of TAP-binding peptide, two orthogonal methods","pmids":["17036044"],"is_preprint":false},{"year":1999,"finding":"SRp20 is essential for mouse development; knockout mice fail to form blastocysts and die at the morula stage. Immunofluorescent staining showed SRp20 is present in oocytes and early embryonic stages, demonstrating a non-redundant function among SR proteins.","method":"Cre-loxP conditional knockout in mice, immunofluorescence staining","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with clear developmental phenotype, in vivo localization data","pmids":["10469594"],"is_preprint":false},{"year":2009,"finding":"SRp20 and ASF/SF2 associate with interphase chromatin but are released from hyperphosphorylated mitotic chromosomes. Aurora B kinase-mediated histone H3 serine 10 phosphorylation is the mechanism driving this dissociation, as Aurora B inhibition increased SRp20 and ASF/SF2 retention on mitotic chromosomes.","method":"siRNA knockdown, Aurora B kinase inhibition, chromatin fractionation, immunofluorescence","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — kinase inhibitor combined with chromatin fractionation and knockdown, mechanistic link to H3S10 phosphorylation established","pmids":["19250906"],"is_preprint":false},{"year":2012,"finding":"SRSF3 regulates alternative splicing of TP53 pre-mRNA by binding (via CLIP and RNA pulldown) to the alternatively spliced exon uniquely included in p53β mRNA. Knockdown of SRSF3 induces inclusion of the p53β-specific exon, upregulates p53β protein, and promotes cellular senescence; p53 knockdown partially rescues SRSF3-knockdown-induced senescence.","method":"siRNA knockdown, RNA pulldown assays, CLIP, TP53 minigene splicing assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (CLIP, RNA pulldown, minigene, epistasis with p53 knockdown) in one study","pmids":["22777358"],"is_preprint":false},{"year":2013,"finding":"Hepatocyte-specific deletion of Srsf3 in mice disrupts hepatic architecture and causes impaired hepatocyte maturation with alterations in glucose and lipid homeostasis. Loss of SRSF3 causes aberrant splicing of Hnf1α, Ern1, Hmgcs1, Dhcr7, and Scap, which are critical regulators of glucose and lipid metabolism.","method":"Hepatocyte-specific conditional knockout mice, splicing analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO with defined splicing targets and metabolic phenotype in vivo","pmids":["23299886"],"is_preprint":false},{"year":2019,"finding":"Palmitic acid-induced oxidative stress causes NEDD8 conjugation (neddylation) to SRSF3 at lysine 11, leading to proteasome-mediated degradation. The K11R mutation prevents both SRSF3 degradation and alterations in RNA splicing, and prevention of SRSF3 degradation in vivo partially protects mice from hepatic steatosis, fibrosis and inflammation.","method":"Neddylation assay, site-directed mutagenesis (K11R), proteasome inhibitor treatment, in vivo mouse model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis identifying specific modification site, reconstituted mechanism with in vivo validation","pmids":["31393851"],"is_preprint":false},{"year":2018,"finding":"SRSF3 recruits DROSHA to the basal junction of primary microRNA transcripts (pri-miRNAs) in a CNNC-motif-dependent manner, enhancing Microprocessor cleavage activity. This stimulation only occurs when CNNC is located ~17 nt from the Microprocessor cleavage site.","method":"Pri-miRNA substrate engineering, Microprocessor cleavage assays, SRSF3-DROSHA recruitment assays","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with defined substrates and positional requirements established","pmids":["29615481"],"is_preprint":false},{"year":2013,"finding":"SRSF3 represses translation of PDCD4 mRNA by directly binding to its 5'-UTR. SRSF3 co-localizes with PDCD4 mRNA in P-bodies in live cells; SRSF3 silencing shifts PDCD4 mRNA to translating polysome fractions, and overexpression shifts it to non-translating fractions. Also regulates alternative splicing pattern of PDCD4 pre-mRNA.","method":"Polysome profiling, live cell imaging, RNA reporter systems, siRNA knockdown/overexpression","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — polysome profiling, two reporter systems, live cell imaging in single study with orthogonal approaches","pmids":["24292556"],"is_preprint":false},{"year":2011,"finding":"SRp20 dramatically re-localizes from the nucleus to the cytoplasm during poliovirus infection and partially co-localizes with PCBP2. SRp20 is found in viral translation initiation complexes bound to poliovirus RNA via PCBP2. A mutant SRp20 lacking the RNA recognition motif (SRp20ΔRRM) causes ~100-fold decrease in virus yield, demonstrating the RRM is required for IRES-dependent translation.","method":"Immunofluorescence co-localization, co-immunoprecipitation, dominant-negative mutant expression, virus yield assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RRM deletion mutant combined with co-IP, localization, and functional virus yield assay","pmids":["21779168"],"is_preprint":false},{"year":2008,"finding":"SRp20 and CUG-BP1 act antagonistically to regulate insulin receptor exon 11 alternative splicing. SRp20 binds to exonic splicing enhancers in exon 11 (identified by RNA affinity chromatography) and promotes exon inclusion; overexpression/knockdown confirmed this. The relative ratio of SRp20 to CUG-BP1 in different cells determines degree of exon inclusion.","method":"Minigene linker-scanning mutagenesis, RNA affinity chromatography, overexpression and knockdown","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RNA affinity chromatography plus gain/loss-of-function experiments in multiple cell types","pmids":["19047369"],"is_preprint":false},{"year":2015,"finding":"PTBP1 and PTBP2 bind to an exonic splicing suppressor in SRSF3 exon 4 and inhibit its inclusion, resulting in overexpression of full-length functional SRSF3. Overexpressed SRSF3 in turn promotes PTBP2 expression, forming a regulatory circuit that impairs SRSF3 autoregulation in cancer cells.","method":"RNA binding assays, overexpression/knockdown, RT-PCR splicing analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, binding and functional assays, mechanistic circuit defined but not independently replicated","pmids":["26416554"],"is_preprint":false},{"year":2010,"finding":"SRp20 promotes nucleocytoplasmic export of HSV-1 mRNAs. siRNA knockdown of SRp20 resulted in ~10-fold decrease in HSV-1 virus yields and nuclear accumulation of polyA+ RNA and newly transcribed viral RNA. SRp20 interacts with export receptor TAP/NXF1.","method":"siRNA knockdown, virus yield assays, nuclear/cytoplasmic RNA fractionation, BrU-labeled RNA tracking","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, multiple readouts but mechanistic detail limited to known TAP interaction","pmids":["20227104"],"is_preprint":false},{"year":2010,"finding":"EBV SM protein interacts with SRp20 (identified by affinity purification and mass spectrometry) and recruits/co-opts SRp20 function in alternative splicing of STAT1 pre-mRNA. SRp20 overexpression enhanced SM-mediated alternative splicing; SRp20 knockdown inhibited the SM splicing effect. The interaction regions of SM and SRp20 were mapped by in vitro and in vivo assays.","method":"Affinity purification, mass spectrometry, co-immunoprecipitation, overexpression and knockdown, STAT1 splicing assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction confirmed by Co-IP, with functional validation, single lab","pmids":["20810723"],"is_preprint":false},{"year":2014,"finding":"KSHV ORF57 N-terminal half binds to the RNA recognition motif of SRSF3, preventing SRSF3 from associating with the K8β intron RNA. In the absence of ORF57, SRSF3 binds to a suboptimal K8β intron and inhibits splicing; knockdown of SRSF3 promotes K8β splicing mimicking ORF57. ORF57 also promotes splicing of heterologous transcripts negatively regulated by SRSF3.","method":"Co-immunoprecipitation, RNA binding assays, siRNA knockdown, splicing reporter assays","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain mapping combined with functional splicing assays, mechanistic model supported by knockdown mimicry","pmids":["25234929"],"is_preprint":false},{"year":2019,"finding":"Loss of SRSF3 in cardiomyocytes causes alternative splicing of mTOR mRNA generating a shorter isoform lacking catalytic activity, decreased 4E-BP1 phosphorylation, and consequently increased decapping of mRNAs encoding sarcomeric and calcium-handling proteins, leading to severe systolic dysfunction and death within 8 days. mTOR activation partially reverses decapping.","method":"Inducible cardiomyocyte-specific Srsf3 knockout mice, RNA-Seq, Western blotting, mTOR activation rescue","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with mechanistic pathway (SRSF3→mTOR splicing→4E-BP1→decapping) supported by rescue experiment","pmids":["31145021"],"is_preprint":false},{"year":2018,"finding":"SRSF3 is an essential regulator of alternative splicing and transposable element repression in mouse oocytes. Conditional deletion of Srsf3 compromises germinal vesicle breakdown (GVBD) and meiotic entry. The GVBD defect is caused by both aberrant alternative splicing and derepression of B2 SINE transposable elements.","method":"Conditional oocyte-specific knockout, 3D time-lapse confocal live imaging, single-cell RNA-seq, antisense oligonucleotides, RNase-H gapmers","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches including live imaging, single-cell sequencing, and rescue oligonucleotides in a single study","pmids":["29928511"],"is_preprint":false},{"year":2008,"finding":"SRp20 controls the papillomavirus early-to-late switch by interacting with A/C-rich RNA elements (SE4) and suppressing selection of a late-specific BPV-1 splice site. SRp20 levels inversely correlate with L1 capsid protein expression; abundant SRp20 in undifferentiated keratinocytes promotes viral early E6/E7 expression by enhancing SP1 transcription factor expression.","method":"RNA-protein binding assays, transfection of BPV-1/HPV constructs, raft culture differentiation, knockdown/overexpression","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, RNA binding combined with splicing and expression assays, functional link established","pmids":["18945760"],"is_preprint":false},{"year":2008,"finding":"Beta-catenin/TCF4 signaling activates SRp20 gene transcription; activated beta-catenin mutants increase endogenous SRp20 transcript and protein and stimulate an SRp20 promoter luciferase reporter. The beta-catenin/TCF4-mediated increase in SRp20 protein is sufficient to modulate alternative splicing of CD44 and a control minigene.","method":"Transfection of activated beta-catenin mutants, dominant-negative TCF4, luciferase reporter, endogenous splicing analysis","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, multiple assays but limited to expression/splicing readouts without direct binding to promoter shown","pmids":["18952824"],"is_preprint":false},{"year":2010,"finding":"SRp20 and SRp75 associate with hundreds of distinct, functionally related endogenous mRNA targets in cycling and neurally induced P19 cells, with mRNA target profiles changing in response to neural differentiation. Knockdown of SRp20 led to up- or downregulation of specific target transcripts.","method":"GFP-tagged SR protein immunopurification, genome-wide mRNA target identification, knockdown with GFP rescue","journal":"Nature structural & molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide mRNP immunopurification with functional rescue validation, single lab","pmids":["20639886"],"is_preprint":false},{"year":2012,"finding":"Poliovirus 2A proteinase expression is sufficient to cause nucleocytoplasmic redistribution of SRp20 by cleaving specific nuclear pore proteins. Coxsackievirus B3 similarly relocalizes SRp20 to the cytoplasm. Human rhinovirus 16 2A proteinase alone can efficiently cause SRp20 cytoplasmic relocalization despite lower relocalization during actual rhinovirus infection.","method":"2A proteinase expression constructs, nuclear pore protein cleavage analysis, immunofluorescence","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, viral proteinase expression with mechanistic nuclear pore cleavage data","pmids":["23255796"],"is_preprint":false},{"year":2019,"finding":"Truncated forms of SRSF3 (SRSF3-TR), generated when splicing regulator SLU7 is knocked down, impair correct splicing and expression of SRSF1/ASF/SF2 and the sister chromatid cohesion protein sororin, acting as dominant negatives or via gain-of-function. This pathway links SLU7 to genome stability maintenance.","method":"siRNA knockdown (SLU7), RT-PCR splicing analysis, mouse liver in vivo validation","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis defined genetically in cancer cells and normal mouse liver, multiple downstream targets validated","pmids":["30657957"],"is_preprint":false},{"year":2017,"finding":"In activated microglia, SRSF3 suppresses translation of highly upregulated innate immune transcripts through a 3' UTR-mediated mechanism. Ribosome profiling in vivo revealed dissociation between the mRNA and protein networks, with SRSF3 acting as a translational checkpoint for pro-inflammatory mRNAs.","method":"In vivo ribosome profiling (translational state analysis), innate immune challenge model","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo ribosome profiling with defined 3'UTR mechanism, single lab","pmids":["29241548"],"is_preprint":false},{"year":2018,"finding":"TDP43 and SRSF3 form a complex (TDP43/SRSF3) that controls specific alternative splicing events including PAR3 (controlling metastasis) and NUMB exon 12 (controlling proliferation) in triple-negative breast cancer. Deep sequencing revealed most TDP43-regulated splicing events involve SRSF3.","method":"Co-immunoprecipitation, RNA-seq, knockdown experiments with specific splicing readouts","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP combined with RNA-seq and functional splicing validation, single lab","pmids":["29581274"],"is_preprint":false},{"year":2018,"finding":"SRSF3 regulates PKM pre-mRNA alternative splicing (exon skipping to favor PKM2 over PKM1) in colon cancer cells in cooperation with PTBP1 and hnRNPA1. This was validated by RNP immunoprecipitation and co-immunoprecipitation. SRSF3 silencing increases the PKM1/PKM2 ratio and causes a metabolic shift from glycolysis to oxidative phosphorylation.","method":"RNP immunoprecipitation (RIP), co-immunoprecipitation, siRNA knockdown, metabolic analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RIP and Co-IP with functional metabolic readout, single lab","pmids":["30279379"],"is_preprint":false},{"year":2015,"finding":"SRSF3 and hnRNP H1 regulate alternative splicing at a HER2 splicing hotspot. SRSF3 knockdown switches splicing from the oncogenic Δ16HER2 variant to the anti-proliferative p100 variant. SRSF3 directly binds RNA within HER2 exon 15, with two binding sites identified by RNA chromatography.","method":"siRNA knockdown, RNA chromatography binding assays","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RNA chromatography binding plus functional splicing switch, single lab","pmids":["26367347"],"is_preprint":false},{"year":2021,"finding":"SRSF3 and SRSF7 bind upstream of proximal polyadenylation sites and have opposing effects on 3'UTR length: SRSF3 promotes distal PAS usage (long 3'UTRs) directly by counteracting SRSF7, and indirectly by maintaining high levels of cleavage factor Im (CFIm) via alternative splicing. Upon SRSF3 depletion, CFIm levels decrease and 3'UTRs are shortened.","method":"iCLIP, 3'-end sequencing, siRNA knockdown, domain analysis comparing SRSF3 and SRSF7","journal":"Genome biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — iCLIP combined with 3'-end sequencing and mechanistic dissection of indirect CFIm pathway, single lab with two orthogonal genomic methods","pmids":["33706811"],"is_preprint":false},{"year":2019,"finding":"SRSF3 regulates alternative RNA splicing of ILF3 by binding to RNA sequence motifs, controlling exclusion/inclusion of ILF3 exon 18 or selection of an alternative 3' splice site within exon 18. Reduced SRSF3 leads to production of aberrant ILF3 isoforms 5 and 7 that suppress cell proliferation.","method":"RNA binding assays, minigene splicing assays, overexpression and knockdown","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RNA binding plus minigene with functional isoform characterization, single lab","pmids":["30796096"],"is_preprint":false},{"year":2021,"finding":"Srsf3 is phosphorylated at Akt consensus sites downstream of PI3K-mediated PDGFRα signaling in mouse palatal mesenchyme cells, leading to its nuclear translocation. Ablation of Srsf3 in neural crest lineage leads to facial clefting due to defective cranial neural crest cell proliferation and survival. Srsf3 regulates alternative RNA splicing of transcripts encoding protein kinases to modulate PDGFRα-dependent intracellular signaling.","method":"Phosphorylation assays, conditional neural crest knockout mice, alternative splicing analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — phosphorylation-localization coupling combined with tissue-specific KO and splicing targets, multiple methods","pmids":["34184034"],"is_preprint":false},{"year":2021,"finding":"PPM1G protein phosphatase interacts with SRSF3, promotes its dephosphorylation, and changes alternative splicing patterns of cell cycle and transcriptional regulation genes in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation, overexpression/knockdown, phosphorylation assays, alternative splicing analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and phosphorylation assay with splicing readout, single lab","pmids":["34290239"],"is_preprint":false},{"year":2022,"finding":"SRSF3 is essential for megakaryocyte maturation and platelet production. Megakaryocyte-specific deletion of Srsf3 leads to macrothrombocytopenia and megakaryocyte maturation arrest. SRSF3 depletion leads to nuclear accumulation of megakaryocyte mRNAs, and SRSF3 plays a role in sorting cytoplasmic megakaryocyte RNAs into platelets.","method":"Megakaryocyte-specific conditional knockout mice, RNA-seq, mRNA localization analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO with RNA nuclear retention phenotype and platelet loading function defined","pmids":["34852174"],"is_preprint":false},{"year":2018,"finding":"SRSF3 connects alternative polyadenylation with mRNA export. SRSF3 depletion caused preference for proximal poly(A) sites and global 3'UTR shortening associated with senescence-associated pathways. SRSF3 has higher binding density near proximal poly(A) sites than distal ones in 3'UTR-shortened genes.","method":"siRNA knockdown, 3'UTR length analysis, SRSF3 binding density analysis, overexpression of candidate genes","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — binding density analysis combined with functional APA measurements, single lab","pmids":["30835716"],"is_preprint":false},{"year":2018,"finding":"SRSF3 is functionally connected to the nuclear RNA exosome for degradation of intronless mRNAs. SRSF3 interacts with both the RNA exosome and its adaptor complex NEXT to promote degradation of intronless viral and cellular mRNAs in the nucleus.","method":"Co-immunoprecipitation of SRSF3 with exosome and NEXT complex, RNA stability assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP evidence of SRSF3-exosome-NEXT interaction with functional mRNA stability readout, single lab","pmids":["30150655"],"is_preprint":false},{"year":2013,"finding":"SRp20 promotes exon 9 skipping of caspase-2 pre-mRNA by directly binding to a specific sequence on exon 8 (but not mutant sequences), as demonstrated by RNA pulldown. Deletion of 26 nt from exon 8 potential binding site severely disrupts SRSF3-mediated exon 9 skipping.","method":"siRNA knockdown, overexpression, RNA pulldown, deletion and substitution mutagenesis","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RNA pulldown with mutagenesis defining binding site, functional splicing assay, single lab","pmids":["24321384"],"is_preprint":false},{"year":2013,"finding":"Srp20 (SRp20) overexpression increases inclusion of TrkB exon 19 (generating TrkB-Shc transcript) in a TrkB minigene system, and Srp20 knockdown produces the opposite effect. Amyloid beta 1-42 increases Srp20 mRNA levels in SHSY5Y cells, suggesting Srp20 mediates Aβ-induced TrkB splicing changes relevant to Alzheimer's disease.","method":"TrkB minigene transfection, Srp20 overexpression and knockdown, Aβ treatment","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — minigene splicing assay with gain/loss-of-function, single lab","pmids":["22788679"],"is_preprint":false},{"year":2012,"finding":"EBV EB2 protein counteracts SRp20 by enhancing SRp20 association with beta-globin transcripts (shown by RNA-immunoprecipitation), apparently stabilizing labile SRp20-RNA interactions to prevent SRp20-mediated mRNA destabilization. SRp20 depletion increases cytoplasmic accumulation of intronless mRNAs, suggesting SRp20 normally destabilizes these RNAs.","method":"siRNA knockdown, RNA immunoprecipitation (RIP), mRNA accumulation assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RIP combined with functional mRNA stability assay, single lab","pmids":["22505578"],"is_preprint":false},{"year":2023,"finding":"SRSF7 and SRSF3 stimulate Microprocessor cleavage of pri-miRNAs through CRC and CNNC motifs adopting specific secondary structures. Both factors affect Microprocessor cleavage sites in human cells. High-throughput pri-miRNA cleavage assays defined the structural requirements for SRSF3-mediated Microprocessor enhancement.","method":"High-throughput pri-miRNA cleavage assays, Microprocessor assays with SRSF3/SRSF7, human cell experiments","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-throughput in vitro reconstitution with structural requirements defined, consistent with prior mechanistic work (PMID 29615481)","pmids":["36750366"],"is_preprint":false},{"year":2019,"finding":"SRSF3 inhibits expression of BECN1 (Beclin-1), a key autophagy regulator, by suppressing expression of p65 and FoxO1 upstream of BECN1. Overexpression of SRSF3 inhibits hypoxia-induced autophagy while knockdown increases autophagic activity.","method":"Knockdown and overexpression, hypoxia-induced autophagy assay, gene expression analysis","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect mechanism (SRSF3→p65/FoxO1→BECN1) without direct binding shown","pmids":["30654935"],"is_preprint":false},{"year":2005,"finding":"Insulin stimulation causes proteasome-dependent reduction in SRp20 levels in human hematopoietic cells, identifying SRp20 as a downstream effector of insulin signaling degraded via the proteasome.","method":"2D electrophoresis proteomic analysis, Western blotting, MG-132 proteasome inhibitor treatment","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — proteasome inhibitor rescue confirmed by 1D Western blot, single lab","pmids":["15827065"],"is_preprint":false},{"year":2006,"finding":"Nuclear PLCbeta1 physically interacts with SRp20 in the nucleus (demonstrated by co-immunoprecipitation and subcellular fractionation), and overexpression of nuclear PLCbeta1 downregulates SRp20 expression.","method":"Co-immunoprecipitation, subcellular fractionation, 2D Western blotting","journal":"Proteomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with no mechanistic follow-up beyond expression correlation","pmids":["17022104"],"is_preprint":false},{"year":2022,"finding":"SRSF3 promotes influenza A virus replication by binding to viral mRNA and participating in its nuclear-cytoplasmic transport. The 88th amino acid of SRSF3 is required for this function. SRSF3 knockdown reduces viral replication.","method":"RIP, FISH, overexpression/knockdown, site-directed mutagenesis (aa88), virus replication assays","journal":"Veterinary microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RIP and FISH combined with point mutagenesis defining functional residue, single lab","pmids":["35063826"],"is_preprint":false},{"year":2020,"finding":"SRSF3 silencing in glioblastoma cells decreased aggressiveness in vitro and in vivo, likely through a molecular mechanism involving PDGFRB and PI3K-AKT/ERK signaling pathways, possibly involving altered alternative splicing of TP73 transcription factor controlling PDGFRB.","method":"siRNA knockdown, in vitro aggressiveness assays, in vivo tumor growth, splicing analysis","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo tumor reduction with pathway analysis, but PDGFRB-TP73 splicing link not fully mechanistically resolved","pmids":["33141183"],"is_preprint":false},{"year":2023,"finding":"Loss of SRSF3 in hepatocytes impairs lipophagy (selective autophagy of lipid droplets) by promoting proteasomal degradation of syntaxin 17 (STX17), a key autophagosomal SNARE protein required for autophagosome-lysosome fusion. Ubiquitination of STX17 is increased via upregulation of SIAH1 upon SRSF3 loss.","method":"siRNA knockdown, lipophagy assays, ubiquitination assays, protein stability analysis","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ubiquitination and stability assays define mechanism, but SRSF3-STX17 connection is indirect, single lab","pmids":["36764525"],"is_preprint":false},{"year":2013,"finding":"SRp20 is a structural component of stress granules (SGs) and P-bodies (PBs). Knockdown of SRp20 disrupts RNA granule formation. SRp20 is distributed across all ribosomal fractions in polysome profiling, suggesting a role in post-transcriptional cytoplasmic mRNA regulation through RNA granules.","method":"Immunofluorescence microscopy, siRNA knockdown, polysome profiling","journal":"Journal of nanoscience and nanotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — localization confirmed by antibody and tagged protein, functional requirement shown by KD disruption of granules","pmids":["23646715"],"is_preprint":false},{"year":2022,"finding":"hnRNPH1 recruits PTBP2 and SRSF3 to form a complex that modulates alternative splicing in germ cells. Conditional knockout of Hnrnph1 in spermatogenic cells causes aberrant splicing events affecting meiosis-related genes and germ-Sertoli cell communication, leading to infertility. SRSF3 is part of the hnRNPH1 splicing regulatory complex.","method":"Co-immunoprecipitation, conditional knockout mice, splicing analysis, fertility phenotype","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing the complex plus in vivo KO phenotype, but SRSF3 not directly manipulated","pmids":["35739118"],"is_preprint":false}],"current_model":"SRSF3 (SRp20) is a multifunctional SR protein that regulates nearly all aspects of RNA metabolism: it promotes constitutive and alternative pre-mRNA splicing by binding specific CA-rich or CAUC RNA sequences via its RRM domain; autoregulates its own expression by enhancing inclusion of its exon 4 (which encodes a premature stop codon); promotes nuclear export of intronless and polyadenylated mRNAs through a short arginine-rich peptide that directly contacts the export receptor TAP/NXF1; represses translation of specific mRNAs (e.g., PDCD4) by binding their 5'UTR and sequestering them in P-bodies; recruits DROSHA to pri-miRNA basal junctions to stimulate microRNA biogenesis; modulates alternative polyadenylation by competing with SRSF7 for proximal poly(A) site usage; is released from mitotic chromosomes via Aurora B-mediated histone H3 Ser10 phosphorylation; is degraded by neddylation at Lys11 under oxidative/lipotoxic stress; is phosphorylated by Akt downstream of PDGFRα/PI3K signaling leading to nuclear translocation; and is essential for embryonic blastocyst formation, hepatocyte differentiation, megakaryocyte maturation, and oocyte meiotic entry, with its loss in cardiomyocytes causing mTOR alternative splicing, reduced 4E-BP1 phosphorylation, and mRNA decapping-driven heart failure."},"narrative":{"mechanistic_narrative":"SRSF3 (SRp20) is a multifunctional SR-family RNA-binding protein that governs pre-mRNA splicing and couples it to downstream steps of RNA metabolism, recognizing CA-rich/CAUC RNA elements through its RRM in which the 5' cytosine is the principal specificity determinant [PMID:17036044, PMID:10094314]. As a sequence-specific splicing transactivator it controls constitutive and alternative exon choice across many transcripts, including its own pre-mRNA—where it enhances inclusion of the exon 4 that encodes a truncated, RS-domain-less product, an autoregulatory loop antagonized by ASF/SF2 [PMID:9305649, PMID:10094314]. Its splicing decisions are read out on physiologically critical substrates: it directs TP53 isoform choice to restrain senescence [PMID:22777358], insulin receptor exon 11 inclusion antagonistically with CUG-BP1 [PMID:19047369], and caspase-2 exon skipping [PMID:24321384], and it acts within multiprotein splicing complexes with partners such as TDP43, PTBP1/hnRNPA1, and hnRNP H1 [PMID:29581274, PMID:30279379, PMID:26367347]. Beyond splicing, SRSF3 links transcript processing to nuclear export—an arginine-rich peptide adjacent to the RRM contacts the export receptor TAP/NXF1 to drive export of intronless and polyadenylated mRNAs [PMID:17036044, PMID:11336712]—and to 3'-end processing, where it promotes distal poly(A) site usage and long 3'UTRs by counteracting SRSF7 and sustaining CFIm levels [PMID:33706811, PMID:30835716]. It additionally stimulates Microprocessor cleavage of pri-miRNAs by recruiting DROSHA in a CNNC-motif- and position-dependent manner [PMID:29615481, PMID:36750366], and represses translation of specific mRNAs such as PDCD4 via 5'UTR binding and P-body sequestration [PMID:24292556, PMID:23646715]. SRSF3 activity is constrained by post-translational control, including Aurora B-driven H3 Ser10 phosphorylation that releases it from mitotic chromosomes [PMID:19250906] and NEDD8 conjugation at Lys11 that triggers its proteasomal degradation under lipotoxic stress [PMID:31393851]. Genetically, SRSF3 is non-redundant for mouse development and tissue maturation: its loss blocks blastocyst formation [PMID:10469594], impairs hepatocyte maturation and glucose/lipid homeostasis [PMID:23299886], disrupts oocyte meiotic entry with transposon derepression [PMID:29928511], blocks megakaryocyte maturation and platelet RNA loading [PMID:34852174], and in cardiomyocytes triggers an mTOR mis-splicing/4E-BP1/decapping cascade causing fatal heart failure [PMID:31145021].","teleology":[{"year":1997,"claim":"Established that SRSF3 is not merely a generic splicing factor but autoregulates its own abundance, defining a feedback principle for SR-protein homeostasis.","evidence":"Reporter/minigene constructs with overexpression in transfected cells","pmids":["9305649"],"confidence":"High","gaps":["Did not define the RNA element bound","Physiological consequence of the truncated isoform unaddressed"]},{"year":1999,"claim":"Defined the RNA sequence specificity and confirmed SRSF3 acts as a sequence-directed splicing transactivator, linking binding to function.","evidence":"SELEX, UV cross-linking, IP and S100 in vitro complementation with recombinant protein","pmids":["10094314"],"confidence":"High","gaps":["No atomic-resolution basis for specificity yet","Endogenous target repertoire unknown"]},{"year":1999,"claim":"Demonstrated SRSF3 is non-redundant in vivo, showing an essential developmental requirement distinct from other SR proteins.","evidence":"Cre-loxP conditional knockout mice with immunofluorescence","pmids":["10469594"],"confidence":"High","gaps":["Molecular targets driving the morula arrest not identified"]},{"year":1998,"claim":"Extended SRSF3 function beyond splice-site choice to 3'-terminal exon/polyadenylation control, an early hint of its role in 3'-end processing.","evidence":"Wild-type and RS-domain-deletion mutants with polyadenylation factor (CstF) binding assays","pmids":["9710581"],"confidence":"High","gaps":["Direct SRSF3-CstF contact not structurally defined"]},{"year":2001,"claim":"Identified SRSF3 as an export factor for intronless mRNAs, coupling RNA recognition to nucleocytoplasmic transport.","evidence":"UV cross-linking, Xenopus oocyte microinjection and antibody inhibition across two cell systems","pmids":["11336712"],"confidence":"High","gaps":["Export receptor contact not yet mapped at this stage"]},{"year":2006,"claim":"Resolved the structural basis of RNA recognition and the molecular adaptor for export, showing a dedicated arginine-rich peptide contacts TAP/NXF1 independent of RNA binding.","evidence":"NMR solution structure of RRM-CAUC complex plus peptide mutagenesis and TAP binding assays","pmids":["17036044"],"confidence":"High","gaps":["Full-length protein/RS-domain contributions to export not structurally resolved"]},{"year":2006,"claim":"Connected SRSF3 recruitment to transcription machinery, showing the RNA pol II CTD directs SRSF3-mediated exon skipping independent of elongation rate.","evidence":"Alpha-amanitin-resistant CTD mutants with fibronectin reporter minigenes","pmids":["17028590"],"confidence":"High","gaps":["Direct CTD-SRSF3 contact and adaptor not identified"]},{"year":2009,"claim":"Revealed cell-cycle regulation of SRSF3 chromatin association, linking Aurora B/H3S10 phosphorylation to its mitotic release.","evidence":"Aurora B inhibition, chromatin fractionation, siRNA knockdown and immunofluorescence","pmids":["19250906"],"confidence":"High","gaps":["Functional consequence of mitotic eviction for daughter-cell splicing unknown"]},{"year":2010,"claim":"Mapped genome-wide endogenous mRNA targets and showed they shift with differentiation, establishing SRSF3 as a context-dependent post-transcriptional regulator.","evidence":"GFP-tagged SR protein immunopurification with genome-wide target ID and knockdown/rescue in P19 cells","pmids":["20639886"],"confidence":"Medium","gaps":["Single lab","Direct vs indirect targets not distinguished"]},{"year":2012,"claim":"Identified TP53 isoform splicing as a direct SRSF3 target controlling senescence, providing a tumor-relevant functional output.","evidence":"CLIP, RNA pulldown, TP53 minigene and epistasis with p53 knockdown","pmids":["22777358"],"confidence":"High","gaps":["Only partial rescue by p53 depletion implies additional effectors"]},{"year":2013,"claim":"Showed SRSF3 controls hepatocyte maturation and metabolic gene splicing in vivo, defining a tissue-specific physiological role.","evidence":"Hepatocyte-specific conditional knockout mice with splicing analysis of Hnf1a, Ern1, Hmgcs1, Dhcr7, Scap","pmids":["23299886"],"confidence":"High","gaps":["Which mis-spliced target is causal for the architecture defect unresolved"]},{"year":2013,"claim":"Established a direct translational-repression function of SRSF3 distinct from splicing, via 5'UTR binding and P-body sequestration of PDCD4.","evidence":"Polysome profiling, live-cell imaging, RNA reporters and knockdown/overexpression","pmids":["24292556","23646715"],"confidence":"Medium","gaps":["Generality across mRNAs and the P-body recruitment mechanism not defined"]},{"year":2018,"claim":"Defined a non-splicing role in miRNA biogenesis, with SRSF3 recruiting DROSHA to pri-miRNA basal junctions in a motif- and position-dependent manner.","evidence":"Engineered pri-miRNA substrates and Microprocessor cleavage/recruitment assays","pmids":["29615481","36750366"],"confidence":"High","gaps":["Endogenous miRNA repertoire dependence on SRSF3 in vivo incompletely mapped"]},{"year":2018,"claim":"Placed SRSF3 in multiprotein splicing complexes (TDP43, PTBP1/hnRNPA1, hnRNP H1) controlling cancer- and germline-relevant exons.","evidence":"Reciprocal Co-IP, RNA-seq, RIP and knockdown with functional splicing readouts","pmids":["29581274","30279379","35739118"],"confidence":"Medium","gaps":["Stoichiometry and assembly order of these complexes undefined","SRSF3 not directly manipulated in some studies"]},{"year":2019,"claim":"Identified neddylation at Lys11 as a stress-triggered degradation switch coupling lipotoxicity to SRSF3-dependent splicing changes.","evidence":"Neddylation assays, K11R mutagenesis, proteasome inhibition and in vivo mouse steatosis model","pmids":["31393851"],"confidence":"High","gaps":["Identity of the responsible NEDD8 E3 ligase not defined"]},{"year":2019,"claim":"Defined a cardiomyocyte SRSF3→mTOR splicing→4E-BP1→decapping axis whose disruption causes lethal heart failure, linking SRSF3 splicing to mRNA stability and translation control.","evidence":"Inducible cardiomyocyte-specific knockout, RNA-seq, Western blot and mTOR-activation rescue","pmids":["31145021"],"confidence":"High","gaps":["Direct SRSF3 binding on mTOR pre-mRNA not mapped"]},{"year":2021,"claim":"Resolved SRSF3's role in alternative polyadenylation, showing it promotes long 3'UTRs both directly against SRSF7 and indirectly via CFIm maintenance.","evidence":"iCLIP and 3'-end sequencing with knockdown and SRSF3/SRSF7 domain comparison","pmids":["33706811","30835716"],"confidence":"High","gaps":["Determinants of proximal vs distal PAS choice on individual genes incomplete"]},{"year":2021,"claim":"Connected upstream signaling to SRSF3 localization, with Akt phosphorylation downstream of PDGFRα/PI3K driving nuclear translocation and craniofacial development.","evidence":"Phosphorylation assays, neural-crest conditional knockout mice and splicing analysis","pmids":["34184034","34290239"],"confidence":"High","gaps":["Phosphatase (PPM1G) versus kinase balance in vivo not fully integrated"]},{"year":2022,"claim":"Demonstrated SRSF3 is required for megakaryocyte maturation and proper RNA sorting into platelets, extending its export/localization role to hematopoiesis.","evidence":"Megakaryocyte-specific knockout mice with RNA-seq and mRNA localization analysis","pmids":["34852174"],"confidence":"High","gaps":["Mechanism of cytoplasmic RNA sorting into platelets undefined"]},{"year":null,"claim":"How SRSF3's many regulatory outputs (splicing, export, APA, miRNA biogenesis, translation) are coordinately selected within a given cell, and which targets are causal for each tissue phenotype, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking post-translational state to functional output","Causal target hierarchy per tissue not established","Recruitment logic switching SRSF3 between activities unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,5,8,14,30,37]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,8,14,30]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[12,26]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,7,32]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,13,47]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,2,11,30,36]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,3,4,8,14]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[12,19,26]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,9,20,32,34]}],"complexes":["Microprocessor (with DROSHA)","nuclear RNA exosome/NEXT","TDP43/SRSF3 splicing complex","hnRNPH1/PTBP2/SRSF3 complex"],"partners":["NXF1","DROSHA","SRSF7","PTBP1","TDP43","HNRNPH1","PPM1G","PCBP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P84103","full_name":"Serine/arginine-rich splicing factor 3","aliases":["Pre-mRNA-splicing factor SRP20","Splicing factor, arginine/serine-rich 3"],"length_aa":164,"mass_kda":19.3,"function":"Splicing factor, which binds the consensus motif 5'-C[ACU][AU]C[ACU][AC]C-3' within pre-mRNA and promotes specific exons inclusion during alternative splicing (PubMed:17036044, PubMed:26876937, PubMed:32440474). Interaction with YTHDC1, a RNA-binding protein that recognizes and binds N6-methyladenosine (m6A)-containing RNAs, promotes recruitment of SRSF3 to its mRNA-binding elements adjacent to m6A sites within exons (PubMed:26876937). Also functions as an adapter involved in mRNA nuclear export (PubMed:11336712, PubMed:18364396, PubMed:28984244). Binds mRNA which is thought to be transferred to the NXF1-NXT1 heterodimer for export (TAP/NXF1 pathway); enhances NXF1-NXT1 RNA-binding activity (PubMed:11336712, PubMed:18364396). Involved in nuclear export of m6A-containing mRNAs via interaction with YTHDC1: interaction with YTHDC1 facilitates m6A-containing mRNA-binding to both SRSF3 and NXF1, promoting mRNA nuclear export (PubMed:28984244)","subcellular_location":"Nucleus; Nucleus speckle; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P84103/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SRSF3","classification":"Common Essential","n_dependent_lines":1207,"n_total_lines":1208,"dependency_fraction":0.9991721854304636},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SRSF3","total_profiled":1310},"omim":[{"mim_id":"617283","title":"YTH DOMAIN-CONTAINING PROTEIN 1; YTHDC1","url":"https://www.omim.org/entry/617283"},{"mim_id":"605221","title":"SPLICING FACTOR, SERINE/ARGININE-RICH, 10; SRSF10","url":"https://www.omim.org/entry/605221"},{"mim_id":"603364","title":"SPLICING FACTOR, SERINE/ARGININE-RICH, 3; SRSF3","url":"https://www.omim.org/entry/603364"},{"mim_id":"312095","title":"A-KINASE ANCHOR PROTEIN 17A; AKAP17A","url":"https://www.omim.org/entry/312095"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SRSF3"},"hgnc":{"alias_symbol":["SRp20"],"prev_symbol":["SFRS3"]},"alphafold":{"accession":"P84103","domains":[{"cath_id":"3.30.70.330","chopping":"10-79","consensus_level":"high","plddt":80.907,"start":10,"end":79}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P84103","model_url":"https://alphafold.ebi.ac.uk/files/AF-P84103-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P84103-F1-predicted_aligned_error_v6.png","plddt_mean":60.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRSF3","jax_strain_url":"https://www.jax.org/strain/search?query=SRSF3"},"sequence":{"accession":"P84103","fasta_url":"https://rest.uniprot.org/uniprotkb/P84103.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P84103/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P84103"}},"corpus_meta":[{"pmid":"11336712","id":"PMC_11336712","title":"Splicing factors SRp20 and 9G8 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H2a gene to promote nucleocytoplasmic export of intronless mRNAs in mammalian cells and Xenopus oocytes. Antibodies to SRp20 eliminate RNA binding and inhibit export. SRp20 can be UV cross-linked to polyadenylated RNA in both nucleus and cytoplasm of HeLa cells.\",\n      \"method\": \"UV cross-linking, transient transfection, Xenopus oocyte microinjection, antibody inhibition\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (UV cross-linking, microinjection, antibody inhibition) replicated in two cell systems\",\n      \"pmids\": [\"11336712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"SRp20 regulates alternative splicing of its own pre-mRNA by enhancing recognition of the weak splice acceptor of exon 4, leading to exon 4 inclusion and production of a truncated protein lacking the RS domain. ASF/SF2 antagonizes this autoregulation by suppressing use of the exon 4 splice donor.\",\n      \"method\": \"Reporter gene constructs, overexpression, transfection assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple reporter constructs with defined splice site elements, replicated finding of autoregulation\",\n      \"pmids\": [\"9305649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The RNA recognition motif (RRM) of SRp20 recognizes sequences similar to those selected by mutated zinc-knuckle 9G8, and SRp20 acts as an efficient splicing transactivator through its specific RNA targets. Recombinant SRp20 activates splicing in vitro of heterologous exons containing its binding sequences.\",\n      \"method\": \"SELEX, UV cross-linking, immunoprecipitation, S100 complementation with recombinant proteins\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified recombinant proteins, SELEX binding specificity, single lab\",\n      \"pmids\": [\"10094314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SRp20 affects alternative 3'-terminal exon recognition in the calcitonin/CGRP gene via enhancing CstF binding to the alternative polyadenylation site. Wild-type SRp20 enhances exon 4 inclusion, while a mutant lacking the RS domain inhibits exon 4 inclusion by inhibiting CstF binding to the poly(A) site.\",\n      \"method\": \"Transfection with wild-type and mutant SRp20, polyadenylation factor binding assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping mutagenesis combined with binding assays, two functional variants tested\",\n      \"pmids\": [\"9710581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The C-terminal domain (CTD) of RNA polymerase II is required for the inhibitory action of SRp20 on inclusion of a fibronectin cassette exon. The CTD promotes exon skipping by recruiting SRp20 in a manner that is independent of effects on transcription elongation rate.\",\n      \"method\": \"Alpha-amanitin-resistant pol II CTD mutants, fibronectin reporter minigenes\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic CTD mutants combined with reporter minigenes, mechanistic dissection of elongation-independent effect\",\n      \"pmids\": [\"17028590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SRp20 and 9G8 contain a short arginine-rich peptide adjacent to their RRMs that does not contact RNA but is necessary and sufficient for interaction with the mRNA export factor TAP/NXF1. NMR solution structure of SRp20 RRM in complex with 5'CAUC3' RNA revealed that all 4 nt are contacted but only the 5' cytosine is specifically recognized.\",\n      \"method\": \"NMR solution structure, binding assays, peptide mutagenesis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with functional validation of TAP-binding peptide, two orthogonal methods\",\n      \"pmids\": [\"17036044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SRp20 is essential for mouse development; knockout mice fail to form blastocysts and die at the morula stage. Immunofluorescent staining showed SRp20 is present in oocytes and early embryonic stages, demonstrating a non-redundant function among SR proteins.\",\n      \"method\": \"Cre-loxP conditional knockout in mice, immunofluorescence staining\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with clear developmental phenotype, in vivo localization data\",\n      \"pmids\": [\"10469594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SRp20 and ASF/SF2 associate with interphase chromatin but are released from hyperphosphorylated mitotic chromosomes. Aurora B kinase-mediated histone H3 serine 10 phosphorylation is the mechanism driving this dissociation, as Aurora B inhibition increased SRp20 and ASF/SF2 retention on mitotic chromosomes.\",\n      \"method\": \"siRNA knockdown, Aurora B kinase inhibition, chromatin fractionation, immunofluorescence\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase inhibitor combined with chromatin fractionation and knockdown, mechanistic link to H3S10 phosphorylation established\",\n      \"pmids\": [\"19250906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SRSF3 regulates alternative splicing of TP53 pre-mRNA by binding (via CLIP and RNA pulldown) to the alternatively spliced exon uniquely included in p53β mRNA. Knockdown of SRSF3 induces inclusion of the p53β-specific exon, upregulates p53β protein, and promotes cellular senescence; p53 knockdown partially rescues SRSF3-knockdown-induced senescence.\",\n      \"method\": \"siRNA knockdown, RNA pulldown assays, CLIP, TP53 minigene splicing assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (CLIP, RNA pulldown, minigene, epistasis with p53 knockdown) in one study\",\n      \"pmids\": [\"22777358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Hepatocyte-specific deletion of Srsf3 in mice disrupts hepatic architecture and causes impaired hepatocyte maturation with alterations in glucose and lipid homeostasis. Loss of SRSF3 causes aberrant splicing of Hnf1α, Ern1, Hmgcs1, Dhcr7, and Scap, which are critical regulators of glucose and lipid metabolism.\",\n      \"method\": \"Hepatocyte-specific conditional knockout mice, splicing analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO with defined splicing targets and metabolic phenotype in vivo\",\n      \"pmids\": [\"23299886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Palmitic acid-induced oxidative stress causes NEDD8 conjugation (neddylation) to SRSF3 at lysine 11, leading to proteasome-mediated degradation. The K11R mutation prevents both SRSF3 degradation and alterations in RNA splicing, and prevention of SRSF3 degradation in vivo partially protects mice from hepatic steatosis, fibrosis and inflammation.\",\n      \"method\": \"Neddylation assay, site-directed mutagenesis (K11R), proteasome inhibitor treatment, in vivo mouse model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis identifying specific modification site, reconstituted mechanism with in vivo validation\",\n      \"pmids\": [\"31393851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SRSF3 recruits DROSHA to the basal junction of primary microRNA transcripts (pri-miRNAs) in a CNNC-motif-dependent manner, enhancing Microprocessor cleavage activity. This stimulation only occurs when CNNC is located ~17 nt from the Microprocessor cleavage site.\",\n      \"method\": \"Pri-miRNA substrate engineering, Microprocessor cleavage assays, SRSF3-DROSHA recruitment assays\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with defined substrates and positional requirements established\",\n      \"pmids\": [\"29615481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SRSF3 represses translation of PDCD4 mRNA by directly binding to its 5'-UTR. SRSF3 co-localizes with PDCD4 mRNA in P-bodies in live cells; SRSF3 silencing shifts PDCD4 mRNA to translating polysome fractions, and overexpression shifts it to non-translating fractions. Also regulates alternative splicing pattern of PDCD4 pre-mRNA.\",\n      \"method\": \"Polysome profiling, live cell imaging, RNA reporter systems, siRNA knockdown/overexpression\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — polysome profiling, two reporter systems, live cell imaging in single study with orthogonal approaches\",\n      \"pmids\": [\"24292556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SRp20 dramatically re-localizes from the nucleus to the cytoplasm during poliovirus infection and partially co-localizes with PCBP2. SRp20 is found in viral translation initiation complexes bound to poliovirus RNA via PCBP2. A mutant SRp20 lacking the RNA recognition motif (SRp20ΔRRM) causes ~100-fold decrease in virus yield, demonstrating the RRM is required for IRES-dependent translation.\",\n      \"method\": \"Immunofluorescence co-localization, co-immunoprecipitation, dominant-negative mutant expression, virus yield assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RRM deletion mutant combined with co-IP, localization, and functional virus yield assay\",\n      \"pmids\": [\"21779168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SRp20 and CUG-BP1 act antagonistically to regulate insulin receptor exon 11 alternative splicing. SRp20 binds to exonic splicing enhancers in exon 11 (identified by RNA affinity chromatography) and promotes exon inclusion; overexpression/knockdown confirmed this. The relative ratio of SRp20 to CUG-BP1 in different cells determines degree of exon inclusion.\",\n      \"method\": \"Minigene linker-scanning mutagenesis, RNA affinity chromatography, overexpression and knockdown\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA affinity chromatography plus gain/loss-of-function experiments in multiple cell types\",\n      \"pmids\": [\"19047369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PTBP1 and PTBP2 bind to an exonic splicing suppressor in SRSF3 exon 4 and inhibit its inclusion, resulting in overexpression of full-length functional SRSF3. Overexpressed SRSF3 in turn promotes PTBP2 expression, forming a regulatory circuit that impairs SRSF3 autoregulation in cancer cells.\",\n      \"method\": \"RNA binding assays, overexpression/knockdown, RT-PCR splicing analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, binding and functional assays, mechanistic circuit defined but not independently replicated\",\n      \"pmids\": [\"26416554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SRp20 promotes nucleocytoplasmic export of HSV-1 mRNAs. siRNA knockdown of SRp20 resulted in ~10-fold decrease in HSV-1 virus yields and nuclear accumulation of polyA+ RNA and newly transcribed viral RNA. SRp20 interacts with export receptor TAP/NXF1.\",\n      \"method\": \"siRNA knockdown, virus yield assays, nuclear/cytoplasmic RNA fractionation, BrU-labeled RNA tracking\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, multiple readouts but mechanistic detail limited to known TAP interaction\",\n      \"pmids\": [\"20227104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"EBV SM protein interacts with SRp20 (identified by affinity purification and mass spectrometry) and recruits/co-opts SRp20 function in alternative splicing of STAT1 pre-mRNA. SRp20 overexpression enhanced SM-mediated alternative splicing; SRp20 knockdown inhibited the SM splicing effect. The interaction regions of SM and SRp20 were mapped by in vitro and in vivo assays.\",\n      \"method\": \"Affinity purification, mass spectrometry, co-immunoprecipitation, overexpression and knockdown, STAT1 splicing assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction confirmed by Co-IP, with functional validation, single lab\",\n      \"pmids\": [\"20810723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KSHV ORF57 N-terminal half binds to the RNA recognition motif of SRSF3, preventing SRSF3 from associating with the K8β intron RNA. In the absence of ORF57, SRSF3 binds to a suboptimal K8β intron and inhibits splicing; knockdown of SRSF3 promotes K8β splicing mimicking ORF57. ORF57 also promotes splicing of heterologous transcripts negatively regulated by SRSF3.\",\n      \"method\": \"Co-immunoprecipitation, RNA binding assays, siRNA knockdown, splicing reporter assays\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping combined with functional splicing assays, mechanistic model supported by knockdown mimicry\",\n      \"pmids\": [\"25234929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of SRSF3 in cardiomyocytes causes alternative splicing of mTOR mRNA generating a shorter isoform lacking catalytic activity, decreased 4E-BP1 phosphorylation, and consequently increased decapping of mRNAs encoding sarcomeric and calcium-handling proteins, leading to severe systolic dysfunction and death within 8 days. mTOR activation partially reverses decapping.\",\n      \"method\": \"Inducible cardiomyocyte-specific Srsf3 knockout mice, RNA-Seq, Western blotting, mTOR activation rescue\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with mechanistic pathway (SRSF3→mTOR splicing→4E-BP1→decapping) supported by rescue experiment\",\n      \"pmids\": [\"31145021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SRSF3 is an essential regulator of alternative splicing and transposable element repression in mouse oocytes. Conditional deletion of Srsf3 compromises germinal vesicle breakdown (GVBD) and meiotic entry. The GVBD defect is caused by both aberrant alternative splicing and derepression of B2 SINE transposable elements.\",\n      \"method\": \"Conditional oocyte-specific knockout, 3D time-lapse confocal live imaging, single-cell RNA-seq, antisense oligonucleotides, RNase-H gapmers\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches including live imaging, single-cell sequencing, and rescue oligonucleotides in a single study\",\n      \"pmids\": [\"29928511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SRp20 controls the papillomavirus early-to-late switch by interacting with A/C-rich RNA elements (SE4) and suppressing selection of a late-specific BPV-1 splice site. SRp20 levels inversely correlate with L1 capsid protein expression; abundant SRp20 in undifferentiated keratinocytes promotes viral early E6/E7 expression by enhancing SP1 transcription factor expression.\",\n      \"method\": \"RNA-protein binding assays, transfection of BPV-1/HPV constructs, raft culture differentiation, knockdown/overexpression\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, RNA binding combined with splicing and expression assays, functional link established\",\n      \"pmids\": [\"18945760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Beta-catenin/TCF4 signaling activates SRp20 gene transcription; activated beta-catenin mutants increase endogenous SRp20 transcript and protein and stimulate an SRp20 promoter luciferase reporter. The beta-catenin/TCF4-mediated increase in SRp20 protein is sufficient to modulate alternative splicing of CD44 and a control minigene.\",\n      \"method\": \"Transfection of activated beta-catenin mutants, dominant-negative TCF4, luciferase reporter, endogenous splicing analysis\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, multiple assays but limited to expression/splicing readouts without direct binding to promoter shown\",\n      \"pmids\": [\"18952824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SRp20 and SRp75 associate with hundreds of distinct, functionally related endogenous mRNA targets in cycling and neurally induced P19 cells, with mRNA target profiles changing in response to neural differentiation. Knockdown of SRp20 led to up- or downregulation of specific target transcripts.\",\n      \"method\": \"GFP-tagged SR protein immunopurification, genome-wide mRNA target identification, knockdown with GFP rescue\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide mRNP immunopurification with functional rescue validation, single lab\",\n      \"pmids\": [\"20639886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Poliovirus 2A proteinase expression is sufficient to cause nucleocytoplasmic redistribution of SRp20 by cleaving specific nuclear pore proteins. Coxsackievirus B3 similarly relocalizes SRp20 to the cytoplasm. Human rhinovirus 16 2A proteinase alone can efficiently cause SRp20 cytoplasmic relocalization despite lower relocalization during actual rhinovirus infection.\",\n      \"method\": \"2A proteinase expression constructs, nuclear pore protein cleavage analysis, immunofluorescence\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, viral proteinase expression with mechanistic nuclear pore cleavage data\",\n      \"pmids\": [\"23255796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Truncated forms of SRSF3 (SRSF3-TR), generated when splicing regulator SLU7 is knocked down, impair correct splicing and expression of SRSF1/ASF/SF2 and the sister chromatid cohesion protein sororin, acting as dominant negatives or via gain-of-function. This pathway links SLU7 to genome stability maintenance.\",\n      \"method\": \"siRNA knockdown (SLU7), RT-PCR splicing analysis, mouse liver in vivo validation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis defined genetically in cancer cells and normal mouse liver, multiple downstream targets validated\",\n      \"pmids\": [\"30657957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In activated microglia, SRSF3 suppresses translation of highly upregulated innate immune transcripts through a 3' UTR-mediated mechanism. Ribosome profiling in vivo revealed dissociation between the mRNA and protein networks, with SRSF3 acting as a translational checkpoint for pro-inflammatory mRNAs.\",\n      \"method\": \"In vivo ribosome profiling (translational state analysis), innate immune challenge model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo ribosome profiling with defined 3'UTR mechanism, single lab\",\n      \"pmids\": [\"29241548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TDP43 and SRSF3 form a complex (TDP43/SRSF3) that controls specific alternative splicing events including PAR3 (controlling metastasis) and NUMB exon 12 (controlling proliferation) in triple-negative breast cancer. Deep sequencing revealed most TDP43-regulated splicing events involve SRSF3.\",\n      \"method\": \"Co-immunoprecipitation, RNA-seq, knockdown experiments with specific splicing readouts\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP combined with RNA-seq and functional splicing validation, single lab\",\n      \"pmids\": [\"29581274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SRSF3 regulates PKM pre-mRNA alternative splicing (exon skipping to favor PKM2 over PKM1) in colon cancer cells in cooperation with PTBP1 and hnRNPA1. This was validated by RNP immunoprecipitation and co-immunoprecipitation. SRSF3 silencing increases the PKM1/PKM2 ratio and causes a metabolic shift from glycolysis to oxidative phosphorylation.\",\n      \"method\": \"RNP immunoprecipitation (RIP), co-immunoprecipitation, siRNA knockdown, metabolic analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RIP and Co-IP with functional metabolic readout, single lab\",\n      \"pmids\": [\"30279379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SRSF3 and hnRNP H1 regulate alternative splicing at a HER2 splicing hotspot. SRSF3 knockdown switches splicing from the oncogenic Δ16HER2 variant to the anti-proliferative p100 variant. SRSF3 directly binds RNA within HER2 exon 15, with two binding sites identified by RNA chromatography.\",\n      \"method\": \"siRNA knockdown, RNA chromatography binding assays\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RNA chromatography binding plus functional splicing switch, single lab\",\n      \"pmids\": [\"26367347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRSF3 and SRSF7 bind upstream of proximal polyadenylation sites and have opposing effects on 3'UTR length: SRSF3 promotes distal PAS usage (long 3'UTRs) directly by counteracting SRSF7, and indirectly by maintaining high levels of cleavage factor Im (CFIm) via alternative splicing. Upon SRSF3 depletion, CFIm levels decrease and 3'UTRs are shortened.\",\n      \"method\": \"iCLIP, 3'-end sequencing, siRNA knockdown, domain analysis comparing SRSF3 and SRSF7\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — iCLIP combined with 3'-end sequencing and mechanistic dissection of indirect CFIm pathway, single lab with two orthogonal genomic methods\",\n      \"pmids\": [\"33706811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SRSF3 regulates alternative RNA splicing of ILF3 by binding to RNA sequence motifs, controlling exclusion/inclusion of ILF3 exon 18 or selection of an alternative 3' splice site within exon 18. Reduced SRSF3 leads to production of aberrant ILF3 isoforms 5 and 7 that suppress cell proliferation.\",\n      \"method\": \"RNA binding assays, minigene splicing assays, overexpression and knockdown\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RNA binding plus minigene with functional isoform characterization, single lab\",\n      \"pmids\": [\"30796096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Srsf3 is phosphorylated at Akt consensus sites downstream of PI3K-mediated PDGFRα signaling in mouse palatal mesenchyme cells, leading to its nuclear translocation. Ablation of Srsf3 in neural crest lineage leads to facial clefting due to defective cranial neural crest cell proliferation and survival. Srsf3 regulates alternative RNA splicing of transcripts encoding protein kinases to modulate PDGFRα-dependent intracellular signaling.\",\n      \"method\": \"Phosphorylation assays, conditional neural crest knockout mice, alternative splicing analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation-localization coupling combined with tissue-specific KO and splicing targets, multiple methods\",\n      \"pmids\": [\"34184034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PPM1G protein phosphatase interacts with SRSF3, promotes its dephosphorylation, and changes alternative splicing patterns of cell cycle and transcriptional regulation genes in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown, phosphorylation assays, alternative splicing analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and phosphorylation assay with splicing readout, single lab\",\n      \"pmids\": [\"34290239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SRSF3 is essential for megakaryocyte maturation and platelet production. Megakaryocyte-specific deletion of Srsf3 leads to macrothrombocytopenia and megakaryocyte maturation arrest. SRSF3 depletion leads to nuclear accumulation of megakaryocyte mRNAs, and SRSF3 plays a role in sorting cytoplasmic megakaryocyte RNAs into platelets.\",\n      \"method\": \"Megakaryocyte-specific conditional knockout mice, RNA-seq, mRNA localization analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO with RNA nuclear retention phenotype and platelet loading function defined\",\n      \"pmids\": [\"34852174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SRSF3 connects alternative polyadenylation with mRNA export. SRSF3 depletion caused preference for proximal poly(A) sites and global 3'UTR shortening associated with senescence-associated pathways. SRSF3 has higher binding density near proximal poly(A) sites than distal ones in 3'UTR-shortened genes.\",\n      \"method\": \"siRNA knockdown, 3'UTR length analysis, SRSF3 binding density analysis, overexpression of candidate genes\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — binding density analysis combined with functional APA measurements, single lab\",\n      \"pmids\": [\"30835716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SRSF3 is functionally connected to the nuclear RNA exosome for degradation of intronless mRNAs. SRSF3 interacts with both the RNA exosome and its adaptor complex NEXT to promote degradation of intronless viral and cellular mRNAs in the nucleus.\",\n      \"method\": \"Co-immunoprecipitation of SRSF3 with exosome and NEXT complex, RNA stability assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP evidence of SRSF3-exosome-NEXT interaction with functional mRNA stability readout, single lab\",\n      \"pmids\": [\"30150655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SRp20 promotes exon 9 skipping of caspase-2 pre-mRNA by directly binding to a specific sequence on exon 8 (but not mutant sequences), as demonstrated by RNA pulldown. Deletion of 26 nt from exon 8 potential binding site severely disrupts SRSF3-mediated exon 9 skipping.\",\n      \"method\": \"siRNA knockdown, overexpression, RNA pulldown, deletion and substitution mutagenesis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RNA pulldown with mutagenesis defining binding site, functional splicing assay, single lab\",\n      \"pmids\": [\"24321384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Srp20 (SRp20) overexpression increases inclusion of TrkB exon 19 (generating TrkB-Shc transcript) in a TrkB minigene system, and Srp20 knockdown produces the opposite effect. Amyloid beta 1-42 increases Srp20 mRNA levels in SHSY5Y cells, suggesting Srp20 mediates Aβ-induced TrkB splicing changes relevant to Alzheimer's disease.\",\n      \"method\": \"TrkB minigene transfection, Srp20 overexpression and knockdown, Aβ treatment\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — minigene splicing assay with gain/loss-of-function, single lab\",\n      \"pmids\": [\"22788679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"EBV EB2 protein counteracts SRp20 by enhancing SRp20 association with beta-globin transcripts (shown by RNA-immunoprecipitation), apparently stabilizing labile SRp20-RNA interactions to prevent SRp20-mediated mRNA destabilization. SRp20 depletion increases cytoplasmic accumulation of intronless mRNAs, suggesting SRp20 normally destabilizes these RNAs.\",\n      \"method\": \"siRNA knockdown, RNA immunoprecipitation (RIP), mRNA accumulation assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RIP combined with functional mRNA stability assay, single lab\",\n      \"pmids\": [\"22505578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SRSF7 and SRSF3 stimulate Microprocessor cleavage of pri-miRNAs through CRC and CNNC motifs adopting specific secondary structures. Both factors affect Microprocessor cleavage sites in human cells. High-throughput pri-miRNA cleavage assays defined the structural requirements for SRSF3-mediated Microprocessor enhancement.\",\n      \"method\": \"High-throughput pri-miRNA cleavage assays, Microprocessor assays with SRSF3/SRSF7, human cell experiments\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-throughput in vitro reconstitution with structural requirements defined, consistent with prior mechanistic work (PMID 29615481)\",\n      \"pmids\": [\"36750366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SRSF3 inhibits expression of BECN1 (Beclin-1), a key autophagy regulator, by suppressing expression of p65 and FoxO1 upstream of BECN1. Overexpression of SRSF3 inhibits hypoxia-induced autophagy while knockdown increases autophagic activity.\",\n      \"method\": \"Knockdown and overexpression, hypoxia-induced autophagy assay, gene expression analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect mechanism (SRSF3→p65/FoxO1→BECN1) without direct binding shown\",\n      \"pmids\": [\"30654935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Insulin stimulation causes proteasome-dependent reduction in SRp20 levels in human hematopoietic cells, identifying SRp20 as a downstream effector of insulin signaling degraded via the proteasome.\",\n      \"method\": \"2D electrophoresis proteomic analysis, Western blotting, MG-132 proteasome inhibitor treatment\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — proteasome inhibitor rescue confirmed by 1D Western blot, single lab\",\n      \"pmids\": [\"15827065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Nuclear PLCbeta1 physically interacts with SRp20 in the nucleus (demonstrated by co-immunoprecipitation and subcellular fractionation), and overexpression of nuclear PLCbeta1 downregulates SRp20 expression.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, 2D Western blotting\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with no mechanistic follow-up beyond expression correlation\",\n      \"pmids\": [\"17022104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SRSF3 promotes influenza A virus replication by binding to viral mRNA and participating in its nuclear-cytoplasmic transport. The 88th amino acid of SRSF3 is required for this function. SRSF3 knockdown reduces viral replication.\",\n      \"method\": \"RIP, FISH, overexpression/knockdown, site-directed mutagenesis (aa88), virus replication assays\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RIP and FISH combined with point mutagenesis defining functional residue, single lab\",\n      \"pmids\": [\"35063826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SRSF3 silencing in glioblastoma cells decreased aggressiveness in vitro and in vivo, likely through a molecular mechanism involving PDGFRB and PI3K-AKT/ERK signaling pathways, possibly involving altered alternative splicing of TP73 transcription factor controlling PDGFRB.\",\n      \"method\": \"siRNA knockdown, in vitro aggressiveness assays, in vivo tumor growth, splicing analysis\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo tumor reduction with pathway analysis, but PDGFRB-TP73 splicing link not fully mechanistically resolved\",\n      \"pmids\": [\"33141183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of SRSF3 in hepatocytes impairs lipophagy (selective autophagy of lipid droplets) by promoting proteasomal degradation of syntaxin 17 (STX17), a key autophagosomal SNARE protein required for autophagosome-lysosome fusion. Ubiquitination of STX17 is increased via upregulation of SIAH1 upon SRSF3 loss.\",\n      \"method\": \"siRNA knockdown, lipophagy assays, ubiquitination assays, protein stability analysis\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ubiquitination and stability assays define mechanism, but SRSF3-STX17 connection is indirect, single lab\",\n      \"pmids\": [\"36764525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SRp20 is a structural component of stress granules (SGs) and P-bodies (PBs). Knockdown of SRp20 disrupts RNA granule formation. SRp20 is distributed across all ribosomal fractions in polysome profiling, suggesting a role in post-transcriptional cytoplasmic mRNA regulation through RNA granules.\",\n      \"method\": \"Immunofluorescence microscopy, siRNA knockdown, polysome profiling\",\n      \"journal\": \"Journal of nanoscience and nanotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — localization confirmed by antibody and tagged protein, functional requirement shown by KD disruption of granules\",\n      \"pmids\": [\"23646715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"hnRNPH1 recruits PTBP2 and SRSF3 to form a complex that modulates alternative splicing in germ cells. Conditional knockout of Hnrnph1 in spermatogenic cells causes aberrant splicing events affecting meiosis-related genes and germ-Sertoli cell communication, leading to infertility. SRSF3 is part of the hnRNPH1 splicing regulatory complex.\",\n      \"method\": \"Co-immunoprecipitation, conditional knockout mice, splicing analysis, fertility phenotype\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing the complex plus in vivo KO phenotype, but SRSF3 not directly manipulated\",\n      \"pmids\": [\"35739118\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SRSF3 (SRp20) is a multifunctional SR protein that regulates nearly all aspects of RNA metabolism: it promotes constitutive and alternative pre-mRNA splicing by binding specific CA-rich or CAUC RNA sequences via its RRM domain; autoregulates its own expression by enhancing inclusion of its exon 4 (which encodes a premature stop codon); promotes nuclear export of intronless and polyadenylated mRNAs through a short arginine-rich peptide that directly contacts the export receptor TAP/NXF1; represses translation of specific mRNAs (e.g., PDCD4) by binding their 5'UTR and sequestering them in P-bodies; recruits DROSHA to pri-miRNA basal junctions to stimulate microRNA biogenesis; modulates alternative polyadenylation by competing with SRSF7 for proximal poly(A) site usage; is released from mitotic chromosomes via Aurora B-mediated histone H3 Ser10 phosphorylation; is degraded by neddylation at Lys11 under oxidative/lipotoxic stress; is phosphorylated by Akt downstream of PDGFRα/PI3K signaling leading to nuclear translocation; and is essential for embryonic blastocyst formation, hepatocyte differentiation, megakaryocyte maturation, and oocyte meiotic entry, with its loss in cardiomyocytes causing mTOR alternative splicing, reduced 4E-BP1 phosphorylation, and mRNA decapping-driven heart failure.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SRSF3 (SRp20) is a multifunctional SR-family RNA-binding protein that governs pre-mRNA splicing and couples it to downstream steps of RNA metabolism, recognizing CA-rich/CAUC RNA elements through its RRM in which the 5' cytosine is the principal specificity determinant [#5, #2]. As a sequence-specific splicing transactivator it controls constitutive and alternative exon choice across many transcripts, including its own pre-mRNA—where it enhances inclusion of the exon 4 that encodes a truncated, RS-domain-less product, an autoregulatory loop antagonized by ASF/SF2 [#1, #2]. Its splicing decisions are read out on physiologically critical substrates: it directs TP53 isoform choice to restrain senescence [#8], insulin receptor exon 11 inclusion antagonistically with CUG-BP1 [#14], and caspase-2 exon skipping [#37], and it acts within multiprotein splicing complexes with partners such as TDP43, PTBP1/hnRNPA1, and hnRNP H1 [#27, #28, #29]. Beyond splicing, SRSF3 links transcript processing to nuclear export—an arginine-rich peptide adjacent to the RRM contacts the export receptor TAP/NXF1 to drive export of intronless and polyadenylated mRNAs [#5, #0]—and to 3'-end processing, where it promotes distal poly(A) site usage and long 3'UTRs by counteracting SRSF7 and sustaining CFIm levels [#30, #35]. It additionally stimulates Microprocessor cleavage of pri-miRNAs by recruiting DROSHA in a CNNC-motif- and position-dependent manner [#11, #40], and represses translation of specific mRNAs such as PDCD4 via 5'UTR binding and P-body sequestration [#12, #47]. SRSF3 activity is constrained by post-translational control, including Aurora B-driven H3 Ser10 phosphorylation that releases it from mitotic chromosomes [#7] and NEDD8 conjugation at Lys11 that triggers its proteasomal degradation under lipotoxic stress [#10]. Genetically, SRSF3 is non-redundant for mouse development and tissue maturation: its loss blocks blastocyst formation [#6], impairs hepatocyte maturation and glucose/lipid homeostasis [#9], disrupts oocyte meiotic entry with transposon derepression [#20], blocks megakaryocyte maturation and platelet RNA loading [#34], and in cardiomyocytes triggers an mTOR mis-splicing/4E-BP1/decapping cascade causing fatal heart failure [#19].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that SRSF3 is not merely a generic splicing factor but autoregulates its own abundance, defining a feedback principle for SR-protein homeostasis.\",\n      \"evidence\": \"Reporter/minigene constructs with overexpression in transfected cells\",\n      \"pmids\": [\"9305649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the RNA element bound\", \"Physiological consequence of the truncated isoform unaddressed\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined the RNA sequence specificity and confirmed SRSF3 acts as a sequence-directed splicing transactivator, linking binding to function.\",\n      \"evidence\": \"SELEX, UV cross-linking, IP and S100 in vitro complementation with recombinant protein\",\n      \"pmids\": [\"10094314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic-resolution basis for specificity yet\", \"Endogenous target repertoire unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrated SRSF3 is non-redundant in vivo, showing an essential developmental requirement distinct from other SR proteins.\",\n      \"evidence\": \"Cre-loxP conditional knockout mice with immunofluorescence\",\n      \"pmids\": [\"10469594\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets driving the morula arrest not identified\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Extended SRSF3 function beyond splice-site choice to 3'-terminal exon/polyadenylation control, an early hint of its role in 3'-end processing.\",\n      \"evidence\": \"Wild-type and RS-domain-deletion mutants with polyadenylation factor (CstF) binding assays\",\n      \"pmids\": [\"9710581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct SRSF3-CstF contact not structurally defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified SRSF3 as an export factor for intronless mRNAs, coupling RNA recognition to nucleocytoplasmic transport.\",\n      \"evidence\": \"UV cross-linking, Xenopus oocyte microinjection and antibody inhibition across two cell systems\",\n      \"pmids\": [\"11336712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Export receptor contact not yet mapped at this stage\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved the structural basis of RNA recognition and the molecular adaptor for export, showing a dedicated arginine-rich peptide contacts TAP/NXF1 independent of RNA binding.\",\n      \"evidence\": \"NMR solution structure of RRM-CAUC complex plus peptide mutagenesis and TAP binding assays\",\n      \"pmids\": [\"17036044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length protein/RS-domain contributions to export not structurally resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected SRSF3 recruitment to transcription machinery, showing the RNA pol II CTD directs SRSF3-mediated exon skipping independent of elongation rate.\",\n      \"evidence\": \"Alpha-amanitin-resistant CTD mutants with fibronectin reporter minigenes\",\n      \"pmids\": [\"17028590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CTD-SRSF3 contact and adaptor not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed cell-cycle regulation of SRSF3 chromatin association, linking Aurora B/H3S10 phosphorylation to its mitotic release.\",\n      \"evidence\": \"Aurora B inhibition, chromatin fractionation, siRNA knockdown and immunofluorescence\",\n      \"pmids\": [\"19250906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of mitotic eviction for daughter-cell splicing unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapped genome-wide endogenous mRNA targets and showed they shift with differentiation, establishing SRSF3 as a context-dependent post-transcriptional regulator.\",\n      \"evidence\": \"GFP-tagged SR protein immunopurification with genome-wide target ID and knockdown/rescue in P19 cells\",\n      \"pmids\": [\"20639886\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct vs indirect targets not distinguished\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified TP53 isoform splicing as a direct SRSF3 target controlling senescence, providing a tumor-relevant functional output.\",\n      \"evidence\": \"CLIP, RNA pulldown, TP53 minigene and epistasis with p53 knockdown\",\n      \"pmids\": [\"22777358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Only partial rescue by p53 depletion implies additional effectors\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed SRSF3 controls hepatocyte maturation and metabolic gene splicing in vivo, defining a tissue-specific physiological role.\",\n      \"evidence\": \"Hepatocyte-specific conditional knockout mice with splicing analysis of Hnf1a, Ern1, Hmgcs1, Dhcr7, Scap\",\n      \"pmids\": [\"23299886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which mis-spliced target is causal for the architecture defect unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established a direct translational-repression function of SRSF3 distinct from splicing, via 5'UTR binding and P-body sequestration of PDCD4.\",\n      \"evidence\": \"Polysome profiling, live-cell imaging, RNA reporters and knockdown/overexpression\",\n      \"pmids\": [\"24292556\", \"23646715\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality across mRNAs and the P-body recruitment mechanism not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a non-splicing role in miRNA biogenesis, with SRSF3 recruiting DROSHA to pri-miRNA basal junctions in a motif- and position-dependent manner.\",\n      \"evidence\": \"Engineered pri-miRNA substrates and Microprocessor cleavage/recruitment assays\",\n      \"pmids\": [\"29615481\", \"36750366\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous miRNA repertoire dependence on SRSF3 in vivo incompletely mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed SRSF3 in multiprotein splicing complexes (TDP43, PTBP1/hnRNPA1, hnRNP H1) controlling cancer- and germline-relevant exons.\",\n      \"evidence\": \"Reciprocal Co-IP, RNA-seq, RIP and knockdown with functional splicing readouts\",\n      \"pmids\": [\"29581274\", \"30279379\", \"35739118\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and assembly order of these complexes undefined\", \"SRSF3 not directly manipulated in some studies\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified neddylation at Lys11 as a stress-triggered degradation switch coupling lipotoxicity to SRSF3-dependent splicing changes.\",\n      \"evidence\": \"Neddylation assays, K11R mutagenesis, proteasome inhibition and in vivo mouse steatosis model\",\n      \"pmids\": [\"31393851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the responsible NEDD8 E3 ligase not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a cardiomyocyte SRSF3→mTOR splicing→4E-BP1→decapping axis whose disruption causes lethal heart failure, linking SRSF3 splicing to mRNA stability and translation control.\",\n      \"evidence\": \"Inducible cardiomyocyte-specific knockout, RNA-seq, Western blot and mTOR-activation rescue\",\n      \"pmids\": [\"31145021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct SRSF3 binding on mTOR pre-mRNA not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved SRSF3's role in alternative polyadenylation, showing it promotes long 3'UTRs both directly against SRSF7 and indirectly via CFIm maintenance.\",\n      \"evidence\": \"iCLIP and 3'-end sequencing with knockdown and SRSF3/SRSF7 domain comparison\",\n      \"pmids\": [\"33706811\", \"30835716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of proximal vs distal PAS choice on individual genes incomplete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected upstream signaling to SRSF3 localization, with Akt phosphorylation downstream of PDGFRα/PI3K driving nuclear translocation and craniofacial development.\",\n      \"evidence\": \"Phosphorylation assays, neural-crest conditional knockout mice and splicing analysis\",\n      \"pmids\": [\"34184034\", \"34290239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase (PPM1G) versus kinase balance in vivo not fully integrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated SRSF3 is required for megakaryocyte maturation and proper RNA sorting into platelets, extending its export/localization role to hematopoiesis.\",\n      \"evidence\": \"Megakaryocyte-specific knockout mice with RNA-seq and mRNA localization analysis\",\n      \"pmids\": [\"34852174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of cytoplasmic RNA sorting into platelets undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SRSF3's many regulatory outputs (splicing, export, APA, miRNA biogenesis, translation) are coordinately selected within a given cell, and which targets are causal for each tissue phenotype, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking post-translational state to functional output\", \"Causal target hierarchy per tissue not established\", \"Recruitment logic switching SRSF3 between activities unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 5, 8, 14, 30, 37]},\n      {\"term_id\": \"GO:0003729\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 8, 14, 30]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [12, 26]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 7, 32]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 13, 47]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2, 11, 30, 36]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 3, 4, 8, 14]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [12, 19, 26]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 9, 20, 32, 34]}\n    ],\n    \"complexes\": [\"Microprocessor (with DROSHA)\", \"nuclear RNA exosome/NEXT\", \"TDP43/SRSF3 splicing complex\", \"hnRNPH1/PTBP2/SRSF3 complex\"],\n    \"partners\": [\"NXF1\", \"DROSHA\", \"SRSF7\", \"PTBP1\", \"TDP43\", \"HNRNPH1\", \"PPM1G\", \"PCBP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}