{"gene":"SRSF5","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":2018,"finding":"Upon glucose intake, SRSF5 protein is stabilized through Tip60-mediated acetylation on K125, which antagonizes Smurf1-mediated ubiquitylation on the same lysine. Upon glucose starvation, SRSF5 is deacetylated by HDAC1 and ubiquitylated by Smurf1 on K125, leading to proteasomal degradation. Stabilized SRSF5 promotes alternative splicing of CCAR1 to produce the CCAR1S isoform, which enhances glucose consumption and acetyl-CoA production to promote tumor growth.","method":"In vitro acetylation/ubiquitylation assays, site-directed mutagenesis (K125), Co-IP, RNAi knockdown, overexpression in cell lines and xenograft models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including mutagenesis of the specific lysine residue, in vitro modification assays, and in vivo tumor models in a single rigorous study","pmids":["29942010"],"is_preprint":false},{"year":2021,"finding":"CLK1 phosphorylates SRSF5 at Ser250, and this phosphorylation inhibits METTL14 exon10 skipping while promoting Cyclin L2 exon6.3 skipping in pancreatic cancer cells, thereby promoting tumor growth and metastasis and regulating m6A methylation.","method":"Phosphorylation mass spectrometry identifying SRSF5-Ser250 as phosphorylation site, transcriptome sequencing, RIP assays, RNA pulldown, CLIP-qPCR, in vitro and in vivo functional assays","journal":"Journal of hematology & oncology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — phosphorylation site identified by mass spectrometry, confirmed by RNA binding assays and in vivo xenograft models, multiple orthogonal methods in single lab","pmids":["33849617"],"is_preprint":false},{"year":2012,"finding":"SRSF5 affects alternative splicing of Mcl-1 pre-mRNA in MCF-7 breast cancer cells, influencing the balance between pro-apoptotic Mcl-1(S) and anti-apoptotic Mcl-1(L) isoforms.","method":"RNAi knockdown of SRSF5 in MCF-7 cells with RT-PCR analysis of Mcl-1 splice isoform ratios","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, single method (RNAi + isoform analysis), no mechanistic dissection of binding or direct interaction confirmed","pmids":["23284704"],"is_preprint":false},{"year":2018,"finding":"SRSF3 promotes SRSF5 overexpression in oral squamous cell carcinoma cells by impairing the autoregulation mechanism of SRSF5. SRSF5 overexpression transforms immortal rodent fibroblasts to form tumors, and its downregulation retards cell growth, cell cycle progression, and tumor growth.","method":"RNAi knockdown, overexpression, focus formation/tumor formation assays in nude mice, western blotting","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function with defined cellular phenotype replicated in vivo; mechanistic link to SRSF3 by single lab without direct binding assay","pmids":["29857020"],"is_preprint":false},{"year":2024,"finding":"LINC01852 lncRNA promotes TRIM72-mediated ubiquitination and degradation of SRSF5, thereby inhibiting SRSF5-mediated alternative splicing of PKM and decreasing PKM2 production, which induces a metabolic switch from glycolysis to oxidative phosphorylation and reduces chemoresistance in colorectal cancer.","method":"RNA pulldown, RNA immunoprecipitation, in vitro and in vivo functional experiments, ubiquitination assays, cell culture and mouse models","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RIP, pulldown, ubiquitination assay, in vivo) in single lab establishing pathway placement of SRSF5","pmids":["38263157"],"is_preprint":false},{"year":2022,"finding":"CPEB2 binds to and increases SRSF5 mRNA stability in glioma microvascular endothelial cells; increased SRSF5 protein then promotes ETS1 exon inclusion (producing P51-ETS1), which transcriptionally promotes expression of tight junction proteins ZO-1, occludin, and claudin-5 to regulate blood-tumor barrier permeability.","method":"RNA immunoprecipitation, knockdown experiments in in vitro BTB/BBB models and in vivo glioblastoma xenograft mice, western blotting, reporter assays","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple methods (RIP, in vivo knockdown, functional barrier assays) in single lab; mechanistic pathway established","pmids":["36064747"],"is_preprint":false},{"year":2013,"finding":"During erythroid cell differentiation, SRSF5 protein is targeted for proteasome-mediated degradation via its C-terminal RS domain, while SRSF5 mRNA is simultaneously upregulated. The RNA recognition motifs (RRMs) of SRSF5 are sufficient to activate pre-mRNA splicing, but the RS domain is required for proteasomal targeting. Inhibition of CLK kinase family and mutation of AKT phosphorylation site Ser86 had no effect on SRSF5 stability, indicating these pathways are not involved in this proteolytic turnover.","method":"Proteasome chemical inhibition, stable transfection of SRSF5 cDNA constructs, domain deletion/mutation analysis, splicing reporter assays in erythroid cell differentiation system","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping with mutagenesis and proteasome inhibitor experiments, single lab with multiple orthogonal approaches","pmids":["23536862"],"is_preprint":false},{"year":2021,"finding":"Srsf5 knockout mice (generated by CRISPR-Cas9) are perinatally lethal and exhibit noncompaction of ventricular myocardium with cardiac dysfunction. Mechanistically, Srsf5 promotes alternative splicing of Myom1 (myomesin-1) to switch between embryonic and adult isoforms; this switch cannot be completed in Srsf5-deficient hearts.","method":"CRISPR-Cas9 knockout mouse generation, echocardiography, electrocardiography, RNA splicing analysis","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo CRISPR knockout with defined lethal cardiac phenotype and specific splicing target (Myom1) identified; multiple phenotypic readouts","pmids":["34622152"],"is_preprint":false},{"year":2017,"finding":"SRSF5 transcript and protein levels are induced by mild hypothermia (32°C), DNA damage, hypoxia, cycloheximide, and hypotonicity in mammalian cells, identifying it as a cold-inducible protein. SRSF5 facilitates production of p19 H-RAS (an alternative splicing isoform) and increases sensitivity to doxorubicin. Induction of SRSF5 (as well as CIRP and RBM3) depends on TRPV4 channel protein but appears independent of its ion channel activity.","method":"Temperature shift experiments, immunohistochemistry, western blotting, TRPV4 inhibition/knockdown, doxorubicin sensitivity assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple stress conditions tested, TRPV4 dependency established by inhibition, single lab","pmids":["28536481"],"is_preprint":false},{"year":2022,"finding":"SRSF5, via its RRM2 domain, directly binds influenza A virus M mRNA at conserved sites (positions 163, 709, and 712), interacts with U1 snRNP, and promotes M mRNA splicing to produce M2 protein, thereby facilitating viral replication. Mutations at the three binding sites attenuate virus replication and pathogenesis in vivo. SRSF5 conditional knockout in lung protects mice from lethal IAV challenge.","method":"RNA-protein binding assays, domain mutagenesis (RRM2), Co-IP with U1 snRNP, site-directed mutagenesis of binding sites in viral genome, conditional knockout mice, in vivo IAV challenge","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — domain-level mutagenesis, direct binding demonstrated, in vivo knockout phenotype, multiple orthogonal methods in single study","pmids":["36257906"],"is_preprint":false},{"year":2021,"finding":"SRSF5 regulates alternative splicing of DMTF1 pre-mRNA by modulating SF1 binding to the DMTF1 pre-mRNA; SRSF5 binding competes with or modulates SF1 association to influence exon inclusion/skipping.","method":"RIP assays, CLIP-seq, splicing reporter assays, mutagenesis of splicing regulatory elements (ESE/ESS), co-immunoprecipitation","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RIP, CLIP-seq and reporter assays used; single lab, mechanistic model proposed with supporting data","pmids":["34291726"],"is_preprint":false},{"year":2023,"finding":"SRSF5 promotes alternative splicing of NCOR2 pre-mRNA to suppress production of the BQ323636.1 splice variant (exon 11 exclusion isoform). SRPK1 phosphorylates SRSF5, and inhibition of SRPK1 by SRPKIN-1 reduces SRSF5 phosphorylation, enhancing SRSF5 interaction with exon 11 of NCOR2 and reducing BQ mRNA production, thereby reversing tamoxifen resistance in ER-positive breast cancer.","method":"SRSF5 knockdown and overexpression, Co-IP (SRPK1-SRSF5 interaction), in vitro and in vivo studies, tissue microarray, phosphorylation assays with SRPKIN-1 inhibitor","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP for SRPK1-SRSF5 interaction, functional assays in vitro and in vivo, single lab with multiple methods","pmids":["37190199"],"is_preprint":false},{"year":2023,"finding":"SRSF5 knockdown induces apoptosis through activation of caspase-3 in APL (NB4) cells, establishing SRSF5 as a pro-survival factor in leukemia.","method":"siRNA knockdown of SRSF5 in NB4 cells, caspase-3 activation assay, cell viability assays","journal":"Archives of biochemistry and biophysics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (RNAi + caspase assay), no direct mechanistic dissection of splicing targets","pmids":["37356608"],"is_preprint":false},{"year":1997,"finding":"The human SFRS5/SRp40 gene produces two major transcripts (~1.8-kb short form and ~3.3-kb long form) by alternative splicing (intron 5 retention in the long form); the short form encodes the SR splicing factor and at most the long form encodes a truncated protein with one RNA-binding domain. The gene was localized to chromosome 14q24.","method":"cDNA cloning, northern blotting, FISH, somatic cell hybrid PCR, immunofluorescence","journal":"Genomics / Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cDNA characterization, FISH chromosomal localization, two independent papers with consistent findings","pmids":["9244433","9434190"],"is_preprint":false},{"year":2025,"finding":"SRSF5 localizes to both nuclear speckles and the shell of a subset of paraspeckles. SRSF5 binds purine-rich sequences at the 5' end of NEAT1_2, promoting its alignment to paraspeckle shells and enabling large paraspeckle cluster formation during stress. SRSF5 depletion impairs paraspeckle formation; prolonged depletion triggers a feedback loop involving intron retention and premature polyadenylation of TARDBP mRNA, reducing TDP-43 levels and causing NEAT1_2 isoform switching that restores paraspeckle clusters.","method":"Super-resolution microscopy, rapid (acute) depletion system, proximity proteomics, iCLIP, rocaglamide A treatment, immunofluorescence","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — super-resolution imaging combined with iCLIP, proximity proteomics, and acute depletion distinguishing direct from compensatory effects; peer-reviewed publication","pmids":["40716777"],"is_preprint":false},{"year":2025,"finding":"SRSF5 silencing in trophoblast cells (HTR8/SVneo) induces alternative splicing of MLX pre-mRNA, leading to ubiquitination and proteasomal degradation of MLX protein. Loss of MLX enhances NR2F2 transcriptional activity, which inhibits trophoblast cell apoptosis.","method":"RT-PCR for alternative splicing, RIP assays, Co-IP, in vivo ubiquitination assays, siRNA knockdown, CCK8/wound healing/transwell/TUNEL assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RIP and Co-IP used for molecular interactions, ubiquitination assay confirms mechanism, single lab","pmids":["40586738"],"is_preprint":false},{"year":2026,"finding":"The tRNA-derived small RNA CHAtRF directly interacts with SRSF5 and blocks SRSF5 from binding Psmg4 pre-mRNA, thereby promoting exon 2 skipping of Psmg4 and reducing full-length Psmg4 isoform expression, which drives pathological cardiac hypertrophy.","method":"RNA-protein binding assays (CHAtRF-SRSF5 interaction), SRSF5-Psmg4 pre-mRNA binding assays, splicing analysis, in vivo cardiac hypertrophy models, hiPSC-CMs","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct interaction demonstrated, splicing mechanistic pathway established, validated in hiPSC-CMs and in vivo; single lab","pmids":["41907183"],"is_preprint":false}],"current_model":"SRSF5 is a serine/arginine-rich splicing factor that regulates alternative splicing of numerous pre-mRNAs (including CCAR1, Mcl-1, METTL14, Cyclin L2, Myom1, PKM, NCOR2/BQ323636.1, DMTF1, ETS1, MLX, Psmg4, and influenza M mRNA) and whose activity and stability are governed by post-translational modifications: Tip60-mediated acetylation at K125 stabilizes it under high glucose (antagonizing Smurf1/TRIM72-mediated ubiquitin-proteasomal degradation), HDAC1 deacetylates it under starvation triggering degradation, CLK1 phosphorylates it at Ser250 to modulate specific splicing events, SRPK1 phosphorylates it to regulate binding to NCOR2 exon 11, and the RS domain is required for proteasome-mediated turnover during erythroid differentiation; SRSF5 also localizes to nuclear speckles and paraspeckle shells where it binds NEAT1_2 to promote paraspeckle cluster assembly during stress, and its depletion indirectly reduces TDP-43 via premature polyadenylation of TARDBP."},"narrative":{"mechanistic_narrative":"SRSF5 (SFRS5/SRp40) is a serine/arginine-rich splicing factor that controls alternative splicing of numerous pre-mRNAs through sequence-specific RNA binding and modular activity: its tandem RNA recognition motifs are sufficient to activate splicing, while the C-terminal RS domain governs proteasomal turnover [PMID:23536862]. It directs splice-isoform choice across diverse target transcripts, including CCAR1 [PMID:29942010], Mcl-1 [PMID:23284704], METTL14 and Cyclin L2 [PMID:33849617], Myom1 during cardiac development [PMID:34622152], PKM [PMID:38263157], ETS1 [PMID:36064747], DMTF1 (by modulating SF1 binding) [PMID:34291726], NCOR2 exon 11 [PMID:37190199], MLX [PMID:40586738], and Psmg4 [PMID:41907183], frequently doing so by engaging conserved binding sites via its RRM domains [PMID:36257906, PMID:41907183]. SRSF5 activity and abundance are tightly tuned by post-translational modification: glucose-induced Tip60 acetylation at K125 stabilizes SRSF5 by antagonizing Smurf1-mediated ubiquitylation, whereas starvation-driven HDAC1 deacetylation licenses its degradation [PMID:29942010]; phosphorylation by CLK1 at Ser250 and by SRPK1 redirects specific splicing outcomes [PMID:33849617, PMID:37190199]; and ubiquitin ligases such as TRIM72 target it for proteasomal degradation [PMID:38263157]. Beyond intronic splicing, SRSF5 localizes to nuclear speckles and the shell of paraspeckles, where it binds purine-rich sequences at the 5' end of NEAT1_2 to promote paraspeckle cluster assembly during stress, with prolonged loss feeding back through premature polyadenylation of TARDBP to lower TDP-43 [PMID:40716777]. Through these activities SRSF5 acts broadly as a pro-growth/pro-survival factor in cancer and is required for development: Srsf5 knockout mice are perinatally lethal with ventricular noncompaction [PMID:34622152], and SRSF5 is also exploited by influenza A virus to splice M mRNA and generate M2 [PMID:36257906].","teleology":[{"year":1997,"claim":"Established the molecular identity of the gene, defining SFRS5/SRp40 as an SR splicing factor encoded by transcripts whose own production is alternatively spliced.","evidence":"cDNA cloning, northern blotting, FISH and immunofluorescence mapping the gene to chromosome 14q24","pmids":["9244433","9434190"],"confidence":"Medium","gaps":["Functional splicing targets not yet identified","Role of the long intron-5-retaining transcript unresolved"]},{"year":2012,"claim":"First linked SRSF5 to control of an apoptotic effector by showing it shifts Mcl-1 isoform balance, implicating it in cell survival decisions.","evidence":"RNAi knockdown in MCF-7 cells with RT-PCR analysis of Mcl-1 splice isoforms","pmids":["23284704"],"confidence":"Medium","gaps":["No direct binding to Mcl-1 pre-mRNA demonstrated","Single method, single cell line"]},{"year":2013,"claim":"Resolved how SRSF5 domains partition function, showing RRMs drive splicing activation while the RS domain is the determinant of proteasomal turnover during erythroid differentiation.","evidence":"Proteasome inhibition, domain deletion/mutagenesis and splicing reporters in an erythroid differentiation system","pmids":["23536862"],"confidence":"Medium","gaps":["Ubiquitin ligase mediating RS-domain-dependent degradation not identified","CLK and AKT-Ser86 pathways excluded but responsible kinase/E3 unknown"]},{"year":2017,"claim":"Identified SRSF5 as a stress- and cold-inducible protein whose induction depends on TRPV4, connecting splicing regulation to cellular stress responses and drug sensitivity.","evidence":"Temperature-shift and stress-condition assays, TRPV4 inhibition/knockdown, doxorubicin sensitivity assays","pmids":["28536481"],"confidence":"Medium","gaps":["Mechanism of TRPV4-dependent, channel-independent induction unknown","Direct splicing targets of stress-induced SRSF5 not defined"]},{"year":2018,"claim":"Defined the acetylation/ubiquitylation switch on K125 that couples nutrient status to SRSF5 stability and tumor-promoting CCAR1 splicing, providing the core post-translational control logic.","evidence":"In vitro acetylation/ubiquitylation assays, K125 mutagenesis, Co-IP, RNAi, and xenograft models","pmids":["29942010"],"confidence":"High","gaps":["Whether the same switch governs other targets untested","Upstream signal linking glucose to Tip60/HDAC1 incompletely defined"]},{"year":2018,"claim":"Showed SRSF5 overexpression is oncogenic and arises in part from impaired autoregulation promoted by SRSF3, framing SRSF5 dysregulation as a driver of transformation.","evidence":"Knockdown/overexpression, focus and tumor formation assays in nude mice, western blotting","pmids":["29857020"],"confidence":"Medium","gaps":["No direct SRSF3-SRSF5 binding shown","Specific splicing targets mediating transformation not identified"]},{"year":2021,"claim":"Established phosphorylation-directed target selection by CLK1 at Ser250, linking SRSF5 splicing activity to m6A machinery (METTL14) and cell-cycle regulators in pancreatic cancer.","evidence":"Phospho-mass spectrometry, transcriptome sequencing, RIP, RNA pulldown, CLIP-qPCR, in vivo assays","pmids":["33849617"],"confidence":"High","gaps":["How Ser250 phosphorylation alters RNA-binding specificity at structural level unknown","Scope of CLK1-controlled targets beyond two events undefined"]},{"year":2021,"claim":"Demonstrated an essential developmental role in vivo, with SRSF5-dependent Myom1 isoform switching required for cardiac maturation.","evidence":"CRISPR-Cas9 knockout mice with echocardiography, ECG and splicing analysis","pmids":["34622152"],"confidence":"High","gaps":["Whether cardiac phenotype is solely attributable to Myom1 mis-splicing unresolved","Tissue-wide splicing program in knockout hearts not fully mapped"]},{"year":2021,"claim":"Provided a mechanistic model for target-specific splicing by showing SRSF5 modulates SF1 occupancy on DMTF1 pre-mRNA.","evidence":"RIP, CLIP-seq, splicing reporters and mutagenesis of ESE/ESS elements","pmids":["34291726"],"confidence":"Medium","gaps":["Direct competition versus cooperative mechanism with SF1 not fully distinguished","Single lab"]},{"year":2022,"claim":"Placed SRSF5 in a regulatory cascade for the blood-tumor barrier, with CPEB2 stabilizing its mRNA to drive ETS1 splicing and tight-junction gene expression.","evidence":"RIP, knockdown in BTB/BBB models and glioblastoma xenografts, reporter assays","pmids":["36064747"],"confidence":"Medium","gaps":["Direct SRSF5 binding to ETS1 pre-mRNA not shown","Generality beyond glioma endothelium unknown"]},{"year":2022,"claim":"Showed SRSF5 is hijacked by influenza A virus, binding M mRNA via RRM2 at conserved sites and cooperating with U1 snRNP to generate M2 and enable replication.","evidence":"RNA-protein binding, RRM2 mutagenesis, Co-IP with U1 snRNP, viral-site mutagenesis, conditional knockout mice and IAV challenge","pmids":["36257906"],"confidence":"High","gaps":["Host targets co-regulated during infection not catalogued","Therapeutic targetability untested"]},{"year":2023,"claim":"Identified SRPK1 phosphorylation as a tunable lever over NCOR2 exon 11 splicing relevant to endocrine therapy resistance in breast cancer.","evidence":"Knockdown/overexpression, SRPK1-SRSF5 Co-IP, SRPKIN-1 phosphorylation assays, tissue microarray, in vitro and in vivo studies","pmids":["37190199"],"confidence":"Medium","gaps":["Phospho-site on SRSF5 targeted by SRPK1 not mapped","Relationship to CLK1-Ser250 control unclear"]},{"year":2023,"claim":"Reinforced a pro-survival role by showing SRSF5 loss triggers caspase-3-dependent apoptosis in leukemia cells.","evidence":"siRNA knockdown in NB4 cells with caspase-3 and viability assays","pmids":["37356608"],"confidence":"Low","gaps":["No splicing target dissected to explain apoptosis","Single method, single line, no mechanistic link"]},{"year":2024,"claim":"Extended post-translational regulation by identifying LINC01852/TRIM72-mediated ubiquitination of SRSF5 that controls PKM splicing and the glycolysis-to-OXPHOS metabolic switch in colorectal cancer.","evidence":"RNA pulldown, RIP, ubiquitination assays, in vitro and in vivo functional experiments","pmids":["38263157"],"confidence":"Medium","gaps":["Ubiquitylated residue on SRSF5 not defined","Relationship to Smurf1/K125 axis unresolved"]},{"year":2025,"claim":"Revealed a non-splicing structural role for SRSF5 at paraspeckles, binding NEAT1_2 to drive stress-induced cluster assembly with a feedback loop affecting TARDBP/TDP-43.","evidence":"Super-resolution microscopy, acute depletion, proximity proteomics, iCLIP and rocaglamide A treatment","pmids":["40716777"],"confidence":"High","gaps":["How speckle versus paraspeckle partitioning is controlled unknown","Physiological consequences of TDP-43 reduction not delineated"]},{"year":2025,"claim":"Connected SRSF5 to trophoblast survival via MLX splicing, where loss destabilizes MLX and de-represses NR2F2 to limit apoptosis.","evidence":"RT-PCR splicing, RIP, Co-IP, in vivo ubiquitination, siRNA and functional apoptosis/migration assays","pmids":["40586738"],"confidence":"Medium","gaps":["Direct SRSF5 binding site on MLX pre-mRNA not mapped","Single lab, single cell model"]},{"year":2026,"claim":"Showed a tRNA-derived small RNA (CHAtRF) competes with SRSF5 for Psmg4 pre-mRNA binding to drive exon skipping and cardiac hypertrophy, identifying an RNA-based regulator of SRSF5 occupancy.","evidence":"RNA-protein and SRSF5-Psmg4 binding assays, splicing analysis, hiPSC-CMs and in vivo hypertrophy models","pmids":["41907183"],"confidence":"Medium","gaps":["Structural basis of CHAtRF-SRSF5 competition unknown","Generality of small-RNA decoy regulation untested"]},{"year":null,"claim":"How SRSF5's many phosphorylation, acetylation and ubiquitylation events are integrated to select among its diverse pre-mRNA and lncRNA targets in a context-specific manner remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified code linking specific modifications to specific target outcomes","Structural basis of RRM target discrimination unmapped","Interplay between splicing and paraspeckle/scaffolding roles undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[9,10,14,16]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,1,6,7]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[14]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[13,14]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,6,7,9,14]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5]}],"complexes":["nuclear speckles","paraspeckle (shell)"],"partners":["TRIM72","U1 SNRNP","SF1","SRPK1","CLK1","TIP60","SMURF1","HDAC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13243","full_name":"Serine/arginine-rich splicing factor 5","aliases":["Delayed-early protein HRS","Pre-mRNA-splicing factor SRP40","Splicing factor, arginine/serine-rich 5"],"length_aa":272,"mass_kda":31.3,"function":"Plays a role in constitutive splicing and can modulate the selection of alternative splice sites","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q13243/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SRSF5","classification":"Not Classified","n_dependent_lines":41,"n_total_lines":1208,"dependency_fraction":0.03394039735099338},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SRSF5","total_profiled":1310},"omim":[{"mim_id":"614620","title":"INTRAFLAGELLAR TRANSPORT 140; IFT140","url":"https://www.omim.org/entry/614620"},{"mim_id":"604194","title":"SOLUTE CARRIER FAMILY 27 (FATTY ACID TRANSPORTER), MEMBER 4; SLC27A4","url":"https://www.omim.org/entry/604194"},{"mim_id":"600914","title":"SPLICING FACTOR, SERINE/ARGININE-RICH, 5; SRSF5","url":"https://www.omim.org/entry/600914"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SRSF5"},"hgnc":{"alias_symbol":["SRP40","HRS"],"prev_symbol":["SFRS5"]},"alphafold":{"accession":"Q13243","domains":[{"cath_id":"3.30.70.330","chopping":"4-70","consensus_level":"high","plddt":82.2357,"start":4,"end":70},{"cath_id":"3.30.70.330","chopping":"108-177","consensus_level":"high","plddt":78.6923,"start":108,"end":177}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13243","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13243-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13243-F1-predicted_aligned_error_v6.png","plddt_mean":64.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRSF5","jax_strain_url":"https://www.jax.org/strain/search?query=SRSF5"},"sequence":{"accession":"Q13243","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13243.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13243/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13243"}},"corpus_meta":[{"pmid":"33849617","id":"PMC_33849617","title":"CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer.","date":"2021","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33849617","citation_count":102,"is_preprint":false},{"pmid":"23284704","id":"PMC_23284704","title":"Regulation of Mcl-1 by SRSF1 and SRSF5 in cancer cells.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23284704","citation_count":78,"is_preprint":false},{"pmid":"29942010","id":"PMC_29942010","title":"Mutually exclusive acetylation and ubiquitylation of the splicing factor SRSF5 control tumor growth.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29942010","citation_count":77,"is_preprint":false},{"pmid":"29857020","id":"PMC_29857020","title":"SRSF5 functions as a novel oncogenic splicing factor and is upregulated by oncogene SRSF3 in oral squamous cell carcinoma.","date":"2018","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/29857020","citation_count":57,"is_preprint":false},{"pmid":"38263157","id":"PMC_38263157","title":"LINC01852 inhibits the tumorigenesis and chemoresistance in colorectal cancer by suppressing SRSF5-mediated alternative splicing of PKM.","date":"2024","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38263157","citation_count":51,"is_preprint":false},{"pmid":"27565915","id":"PMC_27565915","title":"SRSF5: a novel marker for small-cell lung cancer and pleural metastatic cancer.","date":"2016","source":"Lung cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/27565915","citation_count":46,"is_preprint":false},{"pmid":"36064747","id":"PMC_36064747","title":"CPEB2 m6A methylation regulates blood-tumor barrier permeability by regulating splicing factor SRSF5 stability.","date":"2022","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/36064747","citation_count":30,"is_preprint":false},{"pmid":"28536481","id":"PMC_28536481","title":"TRPV4-dependent induction of a novel mammalian cold-inducible protein SRSF5 as well as CIRP and RBM3.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28536481","citation_count":23,"is_preprint":false},{"pmid":"36257906","id":"PMC_36257906","title":"SRSF5-Mediated Alternative Splicing of M Gene is Essential for Influenza A Virus Replication: A Host-Directed Target Against Influenza Virus.","date":"2022","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/36257906","citation_count":21,"is_preprint":false},{"pmid":"23536862","id":"PMC_23536862","title":"Proteasome-mediated proteolysis of SRSF5 splicing factor intriguingly co-occurs with SRSF5 mRNA upregulation during late erythroid differentiation.","date":"2013","source":"PloS 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SRSF5-Dependent Regulation of Psmg4 Alternative Splicing.","date":"2026","source":"Research (Washington, D.C.)","url":"https://pubmed.ncbi.nlm.nih.gov/41907183","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.01.651415","title":"The biased adenosine-rich content of the HIV-1 genome serves as a molecular signature that facilitates efficient packaging","date":"2025-05-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.01.651415","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.20.648873","title":"TDP-43 toxic gain of function links ALS, FTD and Alzheimer's Disease through splicing dysregulation","date":"2025-04-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.20.648873","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.11.607506","title":"Rapid depletion and super-resolution microscopy reveal an unexpected role of the nuclear-speckle protein SRSF5 in paraspeckle assembly and dynamics during cellular stress","date":"2024-08-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.11.607506","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":28004,"output_tokens":6628,"usd":0.148271,"retried_sync":true,"stage1_stop_reason":"refusal"},"stage2":{"model":"claude-opus-4-8","input_tokens":12771,"output_tokens":5064,"usd":0.095228,"stage2_stop_reason":"end_turn"},"total_usd":0.243499,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"Upon glucose intake, SRSF5 protein is stabilized through Tip60-mediated acetylation on K125, which antagonizes Smurf1-mediated ubiquitylation on the same lysine. Upon glucose starvation, SRSF5 is deacetylated by HDAC1 and ubiquitylated by Smurf1 on K125, leading to proteasomal degradation. Stabilized SRSF5 promotes alternative splicing of CCAR1 to produce the CCAR1S isoform, which enhances glucose consumption and acetyl-CoA production to promote tumor growth.\",\n      \"method\": \"In vitro acetylation/ubiquitylation assays, site-directed mutagenesis (K125), Co-IP, RNAi knockdown, overexpression in cell lines and xenograft models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including mutagenesis of the specific lysine residue, in vitro modification assays, and in vivo tumor models in a single rigorous study\",\n      \"pmids\": [\"29942010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CLK1 phosphorylates SRSF5 at Ser250, and this phosphorylation inhibits METTL14 exon10 skipping while promoting Cyclin L2 exon6.3 skipping in pancreatic cancer cells, thereby promoting tumor growth and metastasis and regulating m6A methylation.\",\n      \"method\": \"Phosphorylation mass spectrometry identifying SRSF5-Ser250 as phosphorylation site, transcriptome sequencing, RIP assays, RNA pulldown, CLIP-qPCR, in vitro and in vivo functional assays\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — phosphorylation site identified by mass spectrometry, confirmed by RNA binding assays and in vivo xenograft models, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"33849617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SRSF5 affects alternative splicing of Mcl-1 pre-mRNA in MCF-7 breast cancer cells, influencing the balance between pro-apoptotic Mcl-1(S) and anti-apoptotic Mcl-1(L) isoforms.\",\n      \"method\": \"RNAi knockdown of SRSF5 in MCF-7 cells with RT-PCR analysis of Mcl-1 splice isoform ratios\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (RNAi + isoform analysis), no mechanistic dissection of binding or direct interaction confirmed\",\n      \"pmids\": [\"23284704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SRSF3 promotes SRSF5 overexpression in oral squamous cell carcinoma cells by impairing the autoregulation mechanism of SRSF5. SRSF5 overexpression transforms immortal rodent fibroblasts to form tumors, and its downregulation retards cell growth, cell cycle progression, and tumor growth.\",\n      \"method\": \"RNAi knockdown, overexpression, focus formation/tumor formation assays in nude mice, western blotting\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function with defined cellular phenotype replicated in vivo; mechanistic link to SRSF3 by single lab without direct binding assay\",\n      \"pmids\": [\"29857020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LINC01852 lncRNA promotes TRIM72-mediated ubiquitination and degradation of SRSF5, thereby inhibiting SRSF5-mediated alternative splicing of PKM and decreasing PKM2 production, which induces a metabolic switch from glycolysis to oxidative phosphorylation and reduces chemoresistance in colorectal cancer.\",\n      \"method\": \"RNA pulldown, RNA immunoprecipitation, in vitro and in vivo functional experiments, ubiquitination assays, cell culture and mouse models\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RIP, pulldown, ubiquitination assay, in vivo) in single lab establishing pathway placement of SRSF5\",\n      \"pmids\": [\"38263157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CPEB2 binds to and increases SRSF5 mRNA stability in glioma microvascular endothelial cells; increased SRSF5 protein then promotes ETS1 exon inclusion (producing P51-ETS1), which transcriptionally promotes expression of tight junction proteins ZO-1, occludin, and claudin-5 to regulate blood-tumor barrier permeability.\",\n      \"method\": \"RNA immunoprecipitation, knockdown experiments in in vitro BTB/BBB models and in vivo glioblastoma xenograft mice, western blotting, reporter assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple methods (RIP, in vivo knockdown, functional barrier assays) in single lab; mechanistic pathway established\",\n      \"pmids\": [\"36064747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"During erythroid cell differentiation, SRSF5 protein is targeted for proteasome-mediated degradation via its C-terminal RS domain, while SRSF5 mRNA is simultaneously upregulated. The RNA recognition motifs (RRMs) of SRSF5 are sufficient to activate pre-mRNA splicing, but the RS domain is required for proteasomal targeting. Inhibition of CLK kinase family and mutation of AKT phosphorylation site Ser86 had no effect on SRSF5 stability, indicating these pathways are not involved in this proteolytic turnover.\",\n      \"method\": \"Proteasome chemical inhibition, stable transfection of SRSF5 cDNA constructs, domain deletion/mutation analysis, splicing reporter assays in erythroid cell differentiation system\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping with mutagenesis and proteasome inhibitor experiments, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"23536862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Srsf5 knockout mice (generated by CRISPR-Cas9) are perinatally lethal and exhibit noncompaction of ventricular myocardium with cardiac dysfunction. Mechanistically, Srsf5 promotes alternative splicing of Myom1 (myomesin-1) to switch between embryonic and adult isoforms; this switch cannot be completed in Srsf5-deficient hearts.\",\n      \"method\": \"CRISPR-Cas9 knockout mouse generation, echocardiography, electrocardiography, RNA splicing analysis\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo CRISPR knockout with defined lethal cardiac phenotype and specific splicing target (Myom1) identified; multiple phenotypic readouts\",\n      \"pmids\": [\"34622152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SRSF5 transcript and protein levels are induced by mild hypothermia (32°C), DNA damage, hypoxia, cycloheximide, and hypotonicity in mammalian cells, identifying it as a cold-inducible protein. SRSF5 facilitates production of p19 H-RAS (an alternative splicing isoform) and increases sensitivity to doxorubicin. Induction of SRSF5 (as well as CIRP and RBM3) depends on TRPV4 channel protein but appears independent of its ion channel activity.\",\n      \"method\": \"Temperature shift experiments, immunohistochemistry, western blotting, TRPV4 inhibition/knockdown, doxorubicin sensitivity assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple stress conditions tested, TRPV4 dependency established by inhibition, single lab\",\n      \"pmids\": [\"28536481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SRSF5, via its RRM2 domain, directly binds influenza A virus M mRNA at conserved sites (positions 163, 709, and 712), interacts with U1 snRNP, and promotes M mRNA splicing to produce M2 protein, thereby facilitating viral replication. Mutations at the three binding sites attenuate virus replication and pathogenesis in vivo. SRSF5 conditional knockout in lung protects mice from lethal IAV challenge.\",\n      \"method\": \"RNA-protein binding assays, domain mutagenesis (RRM2), Co-IP with U1 snRNP, site-directed mutagenesis of binding sites in viral genome, conditional knockout mice, in vivo IAV challenge\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — domain-level mutagenesis, direct binding demonstrated, in vivo knockout phenotype, multiple orthogonal methods in single study\",\n      \"pmids\": [\"36257906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRSF5 regulates alternative splicing of DMTF1 pre-mRNA by modulating SF1 binding to the DMTF1 pre-mRNA; SRSF5 binding competes with or modulates SF1 association to influence exon inclusion/skipping.\",\n      \"method\": \"RIP assays, CLIP-seq, splicing reporter assays, mutagenesis of splicing regulatory elements (ESE/ESS), co-immunoprecipitation\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RIP, CLIP-seq and reporter assays used; single lab, mechanistic model proposed with supporting data\",\n      \"pmids\": [\"34291726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SRSF5 promotes alternative splicing of NCOR2 pre-mRNA to suppress production of the BQ323636.1 splice variant (exon 11 exclusion isoform). SRPK1 phosphorylates SRSF5, and inhibition of SRPK1 by SRPKIN-1 reduces SRSF5 phosphorylation, enhancing SRSF5 interaction with exon 11 of NCOR2 and reducing BQ mRNA production, thereby reversing tamoxifen resistance in ER-positive breast cancer.\",\n      \"method\": \"SRSF5 knockdown and overexpression, Co-IP (SRPK1-SRSF5 interaction), in vitro and in vivo studies, tissue microarray, phosphorylation assays with SRPKIN-1 inhibitor\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP for SRPK1-SRSF5 interaction, functional assays in vitro and in vivo, single lab with multiple methods\",\n      \"pmids\": [\"37190199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SRSF5 knockdown induces apoptosis through activation of caspase-3 in APL (NB4) cells, establishing SRSF5 as a pro-survival factor in leukemia.\",\n      \"method\": \"siRNA knockdown of SRSF5 in NB4 cells, caspase-3 activation assay, cell viability assays\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (RNAi + caspase assay), no direct mechanistic dissection of splicing targets\",\n      \"pmids\": [\"37356608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The human SFRS5/SRp40 gene produces two major transcripts (~1.8-kb short form and ~3.3-kb long form) by alternative splicing (intron 5 retention in the long form); the short form encodes the SR splicing factor and at most the long form encodes a truncated protein with one RNA-binding domain. The gene was localized to chromosome 14q24.\",\n      \"method\": \"cDNA cloning, northern blotting, FISH, somatic cell hybrid PCR, immunofluorescence\",\n      \"journal\": \"Genomics / Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cDNA characterization, FISH chromosomal localization, two independent papers with consistent findings\",\n      \"pmids\": [\"9244433\", \"9434190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SRSF5 localizes to both nuclear speckles and the shell of a subset of paraspeckles. SRSF5 binds purine-rich sequences at the 5' end of NEAT1_2, promoting its alignment to paraspeckle shells and enabling large paraspeckle cluster formation during stress. SRSF5 depletion impairs paraspeckle formation; prolonged depletion triggers a feedback loop involving intron retention and premature polyadenylation of TARDBP mRNA, reducing TDP-43 levels and causing NEAT1_2 isoform switching that restores paraspeckle clusters.\",\n      \"method\": \"Super-resolution microscopy, rapid (acute) depletion system, proximity proteomics, iCLIP, rocaglamide A treatment, immunofluorescence\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — super-resolution imaging combined with iCLIP, proximity proteomics, and acute depletion distinguishing direct from compensatory effects; peer-reviewed publication\",\n      \"pmids\": [\"40716777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SRSF5 silencing in trophoblast cells (HTR8/SVneo) induces alternative splicing of MLX pre-mRNA, leading to ubiquitination and proteasomal degradation of MLX protein. Loss of MLX enhances NR2F2 transcriptional activity, which inhibits trophoblast cell apoptosis.\",\n      \"method\": \"RT-PCR for alternative splicing, RIP assays, Co-IP, in vivo ubiquitination assays, siRNA knockdown, CCK8/wound healing/transwell/TUNEL assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RIP and Co-IP used for molecular interactions, ubiquitination assay confirms mechanism, single lab\",\n      \"pmids\": [\"40586738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The tRNA-derived small RNA CHAtRF directly interacts with SRSF5 and blocks SRSF5 from binding Psmg4 pre-mRNA, thereby promoting exon 2 skipping of Psmg4 and reducing full-length Psmg4 isoform expression, which drives pathological cardiac hypertrophy.\",\n      \"method\": \"RNA-protein binding assays (CHAtRF-SRSF5 interaction), SRSF5-Psmg4 pre-mRNA binding assays, splicing analysis, in vivo cardiac hypertrophy models, hiPSC-CMs\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct interaction demonstrated, splicing mechanistic pathway established, validated in hiPSC-CMs and in vivo; single lab\",\n      \"pmids\": [\"41907183\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SRSF5 is a serine/arginine-rich splicing factor that regulates alternative splicing of numerous pre-mRNAs (including CCAR1, Mcl-1, METTL14, Cyclin L2, Myom1, PKM, NCOR2/BQ323636.1, DMTF1, ETS1, MLX, Psmg4, and influenza M mRNA) and whose activity and stability are governed by post-translational modifications: Tip60-mediated acetylation at K125 stabilizes it under high glucose (antagonizing Smurf1/TRIM72-mediated ubiquitin-proteasomal degradation), HDAC1 deacetylates it under starvation triggering degradation, CLK1 phosphorylates it at Ser250 to modulate specific splicing events, SRPK1 phosphorylates it to regulate binding to NCOR2 exon 11, and the RS domain is required for proteasome-mediated turnover during erythroid differentiation; SRSF5 also localizes to nuclear speckles and paraspeckle shells where it binds NEAT1_2 to promote paraspeckle cluster assembly during stress, and its depletion indirectly reduces TDP-43 via premature polyadenylation of TARDBP.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SRSF5 (SFRS5/SRp40) is a serine/arginine-rich splicing factor that controls alternative splicing of numerous pre-mRNAs through sequence-specific RNA binding and modular activity: its tandem RNA recognition motifs are sufficient to activate splicing, while the C-terminal RS domain governs proteasomal turnover [#6]. It directs splice-isoform choice across diverse target transcripts, including CCAR1 [#0], Mcl-1 [#2], METTL14 and Cyclin L2 [#1], Myom1 during cardiac development [#7], PKM [#4], ETS1 [#5], DMTF1 (by modulating SF1 binding) [#10], NCOR2 exon 11 [#11], MLX [#15], and Psmg4 [#16], frequently doing so by engaging conserved binding sites via its RRM domains [#9, #16]. SRSF5 activity and abundance are tightly tuned by post-translational modification: glucose-induced Tip60 acetylation at K125 stabilizes SRSF5 by antagonizing Smurf1-mediated ubiquitylation, whereas starvation-driven HDAC1 deacetylation licenses its degradation [#0]; phosphorylation by CLK1 at Ser250 and by SRPK1 redirects specific splicing outcomes [#1, #11]; and ubiquitin ligases such as TRIM72 target it for proteasomal degradation [#4]. Beyond intronic splicing, SRSF5 localizes to nuclear speckles and the shell of paraspeckles, where it binds purine-rich sequences at the 5' end of NEAT1_2 to promote paraspeckle cluster assembly during stress, with prolonged loss feeding back through premature polyadenylation of TARDBP to lower TDP-43 [#14]. Through these activities SRSF5 acts broadly as a pro-growth/pro-survival factor in cancer and is required for development: Srsf5 knockout mice are perinatally lethal with ventricular noncompaction [#7], and SRSF5 is also exploited by influenza A virus to splice M mRNA and generate M2 [#9].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established the molecular identity of the gene, defining SFRS5/SRp40 as an SR splicing factor encoded by transcripts whose own production is alternatively spliced.\",\n      \"evidence\": \"cDNA cloning, northern blotting, FISH and immunofluorescence mapping the gene to chromosome 14q24\",\n      \"pmids\": [\"9244433\", \"9434190\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional splicing targets not yet identified\", \"Role of the long intron-5-retaining transcript unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"First linked SRSF5 to control of an apoptotic effector by showing it shifts Mcl-1 isoform balance, implicating it in cell survival decisions.\",\n      \"evidence\": \"RNAi knockdown in MCF-7 cells with RT-PCR analysis of Mcl-1 splice isoforms\",\n      \"pmids\": [\"23284704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct binding to Mcl-1 pre-mRNA demonstrated\", \"Single method, single cell line\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved how SRSF5 domains partition function, showing RRMs drive splicing activation while the RS domain is the determinant of proteasomal turnover during erythroid differentiation.\",\n      \"evidence\": \"Proteasome inhibition, domain deletion/mutagenesis and splicing reporters in an erythroid differentiation system\",\n      \"pmids\": [\"23536862\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin ligase mediating RS-domain-dependent degradation not identified\", \"CLK and AKT-Ser86 pathways excluded but responsible kinase/E3 unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified SRSF5 as a stress- and cold-inducible protein whose induction depends on TRPV4, connecting splicing regulation to cellular stress responses and drug sensitivity.\",\n      \"evidence\": \"Temperature-shift and stress-condition assays, TRPV4 inhibition/knockdown, doxorubicin sensitivity assays\",\n      \"pmids\": [\"28536481\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of TRPV4-dependent, channel-independent induction unknown\", \"Direct splicing targets of stress-induced SRSF5 not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the acetylation/ubiquitylation switch on K125 that couples nutrient status to SRSF5 stability and tumor-promoting CCAR1 splicing, providing the core post-translational control logic.\",\n      \"evidence\": \"In vitro acetylation/ubiquitylation assays, K125 mutagenesis, Co-IP, RNAi, and xenograft models\",\n      \"pmids\": [\"29942010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same switch governs other targets untested\", \"Upstream signal linking glucose to Tip60/HDAC1 incompletely defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed SRSF5 overexpression is oncogenic and arises in part from impaired autoregulation promoted by SRSF3, framing SRSF5 dysregulation as a driver of transformation.\",\n      \"evidence\": \"Knockdown/overexpression, focus and tumor formation assays in nude mice, western blotting\",\n      \"pmids\": [\"29857020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct SRSF3-SRSF5 binding shown\", \"Specific splicing targets mediating transformation not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established phosphorylation-directed target selection by CLK1 at Ser250, linking SRSF5 splicing activity to m6A machinery (METTL14) and cell-cycle regulators in pancreatic cancer.\",\n      \"evidence\": \"Phospho-mass spectrometry, transcriptome sequencing, RIP, RNA pulldown, CLIP-qPCR, in vivo assays\",\n      \"pmids\": [\"33849617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Ser250 phosphorylation alters RNA-binding specificity at structural level unknown\", \"Scope of CLK1-controlled targets beyond two events undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated an essential developmental role in vivo, with SRSF5-dependent Myom1 isoform switching required for cardiac maturation.\",\n      \"evidence\": \"CRISPR-Cas9 knockout mice with echocardiography, ECG and splicing analysis\",\n      \"pmids\": [\"34622152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cardiac phenotype is solely attributable to Myom1 mis-splicing unresolved\", \"Tissue-wide splicing program in knockout hearts not fully mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided a mechanistic model for target-specific splicing by showing SRSF5 modulates SF1 occupancy on DMTF1 pre-mRNA.\",\n      \"evidence\": \"RIP, CLIP-seq, splicing reporters and mutagenesis of ESE/ESS elements\",\n      \"pmids\": [\"34291726\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct competition versus cooperative mechanism with SF1 not fully distinguished\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed SRSF5 in a regulatory cascade for the blood-tumor barrier, with CPEB2 stabilizing its mRNA to drive ETS1 splicing and tight-junction gene expression.\",\n      \"evidence\": \"RIP, knockdown in BTB/BBB models and glioblastoma xenografts, reporter assays\",\n      \"pmids\": [\"36064747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SRSF5 binding to ETS1 pre-mRNA not shown\", \"Generality beyond glioma endothelium unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed SRSF5 is hijacked by influenza A virus, binding M mRNA via RRM2 at conserved sites and cooperating with U1 snRNP to generate M2 and enable replication.\",\n      \"evidence\": \"RNA-protein binding, RRM2 mutagenesis, Co-IP with U1 snRNP, viral-site mutagenesis, conditional knockout mice and IAV challenge\",\n      \"pmids\": [\"36257906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Host targets co-regulated during infection not catalogued\", \"Therapeutic targetability untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified SRPK1 phosphorylation as a tunable lever over NCOR2 exon 11 splicing relevant to endocrine therapy resistance in breast cancer.\",\n      \"evidence\": \"Knockdown/overexpression, SRPK1-SRSF5 Co-IP, SRPKIN-1 phosphorylation assays, tissue microarray, in vitro and in vivo studies\",\n      \"pmids\": [\"37190199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phospho-site on SRSF5 targeted by SRPK1 not mapped\", \"Relationship to CLK1-Ser250 control unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reinforced a pro-survival role by showing SRSF5 loss triggers caspase-3-dependent apoptosis in leukemia cells.\",\n      \"evidence\": \"siRNA knockdown in NB4 cells with caspase-3 and viability assays\",\n      \"pmids\": [\"37356608\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No splicing target dissected to explain apoptosis\", \"Single method, single line, no mechanistic link\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended post-translational regulation by identifying LINC01852/TRIM72-mediated ubiquitination of SRSF5 that controls PKM splicing and the glycolysis-to-OXPHOS metabolic switch in colorectal cancer.\",\n      \"evidence\": \"RNA pulldown, RIP, ubiquitination assays, in vitro and in vivo functional experiments\",\n      \"pmids\": [\"38263157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitylated residue on SRSF5 not defined\", \"Relationship to Smurf1/K125 axis unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a non-splicing structural role for SRSF5 at paraspeckles, binding NEAT1_2 to drive stress-induced cluster assembly with a feedback loop affecting TARDBP/TDP-43.\",\n      \"evidence\": \"Super-resolution microscopy, acute depletion, proximity proteomics, iCLIP and rocaglamide A treatment\",\n      \"pmids\": [\"40716777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How speckle versus paraspeckle partitioning is controlled unknown\", \"Physiological consequences of TDP-43 reduction not delineated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected SRSF5 to trophoblast survival via MLX splicing, where loss destabilizes MLX and de-represses NR2F2 to limit apoptosis.\",\n      \"evidence\": \"RT-PCR splicing, RIP, Co-IP, in vivo ubiquitination, siRNA and functional apoptosis/migration assays\",\n      \"pmids\": [\"40586738\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SRSF5 binding site on MLX pre-mRNA not mapped\", \"Single lab, single cell model\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed a tRNA-derived small RNA (CHAtRF) competes with SRSF5 for Psmg4 pre-mRNA binding to drive exon skipping and cardiac hypertrophy, identifying an RNA-based regulator of SRSF5 occupancy.\",\n      \"evidence\": \"RNA-protein and SRSF5-Psmg4 binding assays, splicing analysis, hiPSC-CMs and in vivo hypertrophy models\",\n      \"pmids\": [\"41907183\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of CHAtRF-SRSF5 competition unknown\", \"Generality of small-RNA decoy regulation untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SRSF5's many phosphorylation, acetylation and ubiquitylation events are integrated to select among its diverse pre-mRNA and lncRNA targets in a context-specific manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified code linking specific modifications to specific target outcomes\", \"Structural basis of RRM target discrimination unmapped\", \"Interplay between splicing and paraspeckle/scaffolding roles undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [9, 10, 14, 16]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 1, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [13, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 6, 7, 9, 14]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"nuclear speckles\", \"paraspeckle (shell)\"],\n    \"partners\": [\"TRIM72\", \"U1 snRNP\", \"SF1\", \"SRPK1\", \"CLK1\", \"Tip60\", \"Smurf1\", \"HDAC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}