{"gene":"SRRM1","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":1999,"finding":"SRm160/300 splicing coactivator is required for a purine-rich exonic splicing enhancer (ESE) to promote splicing of a Drosophila doublesex pre-mRNA. SRm160/300 independently interacts with U2 snRNP and with a human homolog of Transformer 2 (which binds purine-rich ESEs), suggesting it bridges ESE-bound activators with the snRNP spliceosome machinery.","method":"In vitro splicing assays with immunodepletion, co-immunoprecipitation of SRm160/300 with U2 snRNP and Tra2 homolog","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro splicing reconstitution with depletion, reciprocal co-IP for interactions, replicated across multiple labs","pmids":["10339552"],"is_preprint":false},{"year":2000,"finding":"SRm160 is the more critical subunit of the SRm160/300 coactivator for splicing of SRm160/300-dependent pre-mRNAs. Specific depletion of SRm300 does not prevent splicing, whereas addition of recombinant SRm160 alone to SRm160/300-depleted reactions specifically activates splicing.","method":"Specific immunodepletion of SRm300 from splicing extracts; rescue with recombinant SRm160; cDNA isolation and sequence analysis of SRm300","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro splicing reconstitution with depletion and recombinant protein rescue, single lab but multiple orthogonal methods","pmids":["10668804"],"is_preprint":false},{"year":2001,"finding":"SRm160 functions as a general splicing coactivator by interacting with multiple SR family proteins bound to diverse ESE sequences. Multiple SR family and SR-related proteins co-immunoprecipitate specifically with SRm160 under low-salt conditions. Genetic epistasis in C. elegans shows that simultaneous RNAi of CeSRm160 and any individual CeSR family gene produces unfertilized oocytes, demonstrating critical functional interactions in vivo.","method":"Co-immunoprecipitation of SR proteins with SRm160; RNA interference (RNAi) genetic epistasis in C. elegans; in vitro splicing with randomized ESE sequences","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus genetic epistasis in two orthogonal systems, replicated across labs","pmids":["11747818"],"is_preprint":false},{"year":2002,"finding":"SRm160 participates in mRNA 3'-end formation: overexpression promotes 3'-end cleavage in vivo and in vitro. At high levels, SRm160 activates 3'-end cleavage and cytoplasmic accumulation of unspliced pre-mRNAs, uncoupling the splicing requirement for 3'-end formation and nuclear export. SRm160 associates specifically with the cleavage polyadenylation specificity factor (CPSF) and stimulates cleavage of splicing-active pre-mRNAs more efficiently than splicing-inactive ones.","method":"In vivo overexpression assays; in vitro 3'-end cleavage assays; co-immunoprecipitation of SRm160 with CPSF","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro cleavage assay, co-IP with CPSF, in vivo overexpression with mechanistic readout, multiple orthogonal methods","pmids":["11739730"],"is_preprint":false},{"year":2003,"finding":"SRm160 is associated with the nuclear matrix and co-immunoprecipitates with TLS/FUS along with splicing factors PTB (hnRNPI) and SR proteins (SC35, SRp75), suggesting SRm160 participates in spliceosome assembly within the nuclear matrix context.","method":"Co-immunoprecipitation from nuclear extracts; co-immunolocalization; splicing assays with TLS/FUS-immunodepleted extracts","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP with coimmunolocalization, single lab, TLS/FUS-focused study","pmids":["12581738"],"is_preprint":false},{"year":2003,"finding":"SRm160 contains two contiguous domains (amino acids 300–350 and 351–688) that independently target it to nuclear matrix sites at splicing speckled domains. The N-terminal domain localizes SRm160 to the nuclear lamina near sites where mRNA exits the nucleus. These domains were identified as the spatial targeting and nuclear matrix binding domains.","method":"Fluorescence microscopy of FLAG- and EGFP-tagged deletion mutant proteins transfected into cells; nuclear matrix binding assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — systematic deletion mutagenesis with direct subcellular localization imaging, single lab","pmids":["12624182"],"is_preprint":false},{"year":2003,"finding":"SRm160 stimulates 3'-end cleavage independently of its association with the exon junction complex (EJC). EJC components RNPS1, REF, UAP56, and Y14 interact with SRm160, but only SRm160 and RNPS1 stimulate 3'-end cleavage when tethered to transcripts. Assembly of an EJC adjacent to the cleavage/polyadenylation signal in vitro did not significantly affect cleavage efficiency. In C. elegans, simultaneous RNAi of SRm160 and cleavage factor CstF-50 caused late embryonic arrest, demonstrating an evolutionarily conserved functional interaction between SRm160 and the 3'-end cleavage machinery.","method":"In vitro tethered-function assays; in vitro 3'-end cleavage assays with EJC assembly; RNAi epistasis in C. elegans","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro cleavage reconstitution, tethered-function assays, and genetic epistasis in vivo, multiple orthogonal approaches","pmids":["12944400"],"is_preprint":false},{"year":2004,"finding":"SRm160 has ATP-dependent nuclear mobility at splicing speckled domains, revealed by in vitro FRAP in digitonin-permeabilized cells. Both EGFP-labeled and endogenous SRm160 are released from speckle sites by an ATP-dependent mechanism, suggesting SRm160-containing RNA export complexes (but not splicing complexes) have ATP-regulated release. In contrast, SRm300 remains immobile after ATP supplementation.","method":"In vitro FRAP (fluorescence recovery after photobleaching) in digitonin-permeabilized cells; comparison of EGFP-SRm160, endogenous SRm160, RNPS1, and SRm300 mobility","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live-cell imaging with functional perturbation (ATP depletion/addition), single lab, novel in vitro FRAP system","pmids":["15024032"],"is_preprint":false},{"year":2005,"finding":"SRm160-containing complexes are associated with cohesin subunits SMC1alpha, SMC3, RAD21, and SA2. Gradient fractionation revealed two predominant SRm160 complexes: one enriched in splicing components and another enriched in cohesin subunits. Co-immunoprecipitation, co-localization, and combinatorial RNAi in C. elegans support conserved functional interactions between SRm160 and cohesin. SRm160's N-terminal PWI domain mediates its 3'-end processing stimulatory activity.","method":"Immunoaffinity purification + tandem mass spectrometry (gel-free); gradient fractionation; co-immunoprecipitation; co-localization; combinatorial RNAi in C. elegans","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-based interactome plus reciprocal Co-IP plus genetic epistasis in C. elegans, multiple orthogonal methods","pmids":["16159877"],"is_preprint":false},{"year":2006,"finding":"SRm160 regulates CD44 alternative splicing in a Ras-dependent manner: overexpression of SRm160 stimulates inclusion of CD44 variable exon 5 (v5) when Ras is activated, while siRNA-mediated silencing of SRm160 reduces v5 inclusion. SRm160 co-immunoprecipitates with Sam68, a protein that also stimulates v5 inclusion in a Ras-dependent manner, indicating these two proteins interact to regulate CD44 splicing. siRNA depletion of SRm160 reduces CD44 isoform levels and decreases tumor cell invasiveness.","method":"siRNA knockdown; overexpression; co-immunoprecipitation (SRm160 with Sam68); RT-PCR splicing assays; invasion assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, loss-of-function (siRNA) with defined molecular and cellular phenotype, multiple orthogonal methods","pmids":["16354706"],"is_preprint":false},{"year":2014,"finding":"In Drosophila, SRm160 is phosphorylated in vitro by the LAMMER kinase DOA, and DOA kinase alleles suppress overexpression phenotypes of SRm160 in the eye while enhancing genital disc phenotypes, indicating DOA-mediated phosphorylation modifies SRm160 activity. SRm160 overexpression causes apoptosis in the Drosophila eye and is required for somatic sex determination. SRm160 protein is concentrated in nuclei of precellular embryos but is rapidly excluded or degraded upon cellularization.","method":"In vitro kinase assay (DOA phosphorylates SRm160); genetic epistasis (Doa alleles modifying SRm160 overexpression/loss-of-function phenotypes); immunofluorescence localization in embryos","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay plus genetic epistasis, single lab, Drosophila model","pmids":["24907259"],"is_preprint":false},{"year":2017,"finding":"In Drosophila, SRm160 is required in pacemaker neurons for proper circadian oscillations. Reduced SRm160 in adult pacemaker neurons impairs locomotor circadian rhythms and markedly reduces period (per) mRNA levels. The arrhythmicity is rescued by a fully spliced per construct but not by an extra copy of the endogenous per locus, demonstrating that SRm160 positively regulates per levels in a splicing-dependent manner.","method":"Tissue-specific RNAi knockdown in pacemaker neurons; genetic rescue with spliced vs. unspliced per constructs; behavioral assays; neuropeptide immunostaining (PDF/PIGMENT DISPERSING FACTOR)","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with functional rescue experiments, single lab, Drosophila in vivo model","pmids":["28801530"],"is_preprint":false},{"year":2019,"finding":"SRm160 preferentially binds to exonic trinucleotide repeats GCA and AAC, as identified by HITS-CLIP in Drosophila sex-specific cell lines (S2 male, Kc female). Binding was validated by in vitro gel-shift assays and in vivo minigene splicing assays. SRm160 regulates alternative splicing of the sex-determination factor transformer, and 492 differential binding sites between male and female cells were identified, enriched for splicing factor transcripts.","method":"HITS-CLIP (high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation); in vitro gel-shift assay; minigene splicing assays; fly mutant analysis","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — HITS-CLIP for genome-wide RNA binding plus in vitro and in vivo validation, single lab","pmids":["29750417"],"is_preprint":false},{"year":2025,"finding":"SRRM1 promotes an alternative splicing program favoring oncogenic isoforms including NUMB exon 9, identified in a genome-wide CRISPR screen. SRRM1 and SRSF11 share common protein interactors, RNA targets, and oncogenic splicing effects on targets including CD44, MKNK2, ECT2, DIAPH1, KAT5, TCF7L2, FOXM1, and TBX3. Loss of SRRM1 reduces Cyclin D1, Notum, and PRDX2 expression and decreases proliferation, colony formation, and invasion in colorectal and lung cancer cells.","method":"Genome-wide CRISPR screen with NUMB exon 9 splicing reporter; siRNA/shRNA knockdown; proteomics for shared interactors; RNA-seq for splicing targets; cell proliferation, colony formation, and invasion assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus mechanistic follow-up with defined splicing targets and cellular phenotypes, preprint, single lab","pmids":["bio_10.1101_2025.08.20.671097"],"is_preprint":true},{"year":2025,"finding":"SRRM1 (and SRRM2) are potential direct phosphorylation targets of the nuclear speckle-localized kinase TAOK2, as revealed by phosphoproteomics. TAOK2 knockdown perturbs nearly all speckle-resident SR-rich proteins while leaving hnRNPs unperturbed, suggesting SRRM1/2 phosphorylation by TAOK2 plays a structural maintenance role at nuclear speckles that impacts SR protein-driven exon inclusion.","method":"Phosphoproteomics after siRNA knockdown of TAOK2; siRNA knockdown functional readouts (alternative splicing, export, transcript abundance); nuclear speckle imaging","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3–4 / Weak — phosphoproteomics implicates SRRM1 as a target but direct kinase assay for SRRM1 not reported; preprint, single lab","pmids":["bio_10.1101_2025.09.29.679379"],"is_preprint":true},{"year":2025,"finding":"Heterozygous truncating variants in SRRM1 (introduced via CRISPR-Cas9) cause impaired proliferation, migration, and neurite outgrowth in SKNBE2 neuronal cells differentiated in vitro. Pan-neuronal knockdown of Drosophila Srrm1 reduces viability, and motoneuronal knockdown impairs neurological function, establishing a role for SRRM1 in nervous system development.","method":"CRISPR-Cas9 introduction of truncating variants; neuronal differentiation assays; cell proliferation, migration, and neurite morphology quantification; Drosophila pan-neuronal and motoneuronal RNAi knockdown with viability and locomotion assays","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR-engineered loss-of-function with defined cellular phenotypes plus orthogonal in vivo Drosophila model, single study","pmids":["41145827"],"is_preprint":false}],"current_model":"SRRM1 (SRm160) is a serine/arginine-repeat-related nuclear matrix protein that functions as a general splicing coactivator by bridging ESE-bound SR family proteins with the snRNP spliceosome machinery, promotes mRNA 3'-end cleavage via an interaction with CPSF through its PWI domain (independently of the exon junction complex), associates with cohesin subunits, is released from nuclear speckles by an ATP-dependent mechanism, is phosphorylated by LAMMER/TAOK2-family kinases, and regulates cancer-associated alternative splicing events (including CD44 and NUMB isoforms) that influence cell invasion and oncogenic signaling."},"narrative":{"mechanistic_narrative":"SRRM1 (SRm160) is a nuclear matrix-associated serine/arginine-repeat protein that functions as a general splicing coactivator, bridging exonic splicing enhancer (ESE)-bound SR family activators with the snRNP spliceosome to promote pre-mRNA splicing [PMID:10339552, PMID:11747818]. Within the SRm160/300 coactivator it is the catalytically critical subunit, as recombinant SRm160 alone rescues splicing of SRm160/300-dependent pre-mRNAs [PMID:10668804], and it interacts directly with U2 snRNP and a Tra2 homolog to couple ESE recognition to spliceosome assembly [PMID:10339552]. Beyond splicing, SRRM1 stimulates mRNA 3'-end cleavage through association with CPSF, an activity mapped to its N-terminal PWI domain and shown to be independent of the exon junction complex [PMID:11739730, PMID:12944400, PMID:16159877]. It localizes to nuclear speckle splicing domains via discrete spatial-targeting and matrix-binding domains and undergoes ATP-dependent release from these sites, consistent with a role in coupling splicing to mRNA export [PMID:12624182, PMID:15024032]. SRRM1 additionally partitions into a distinct cohesin-associated complex containing SMC1alpha, SMC3, RAD21, and SA2 [PMID:16159877]. Functionally, SRRM1 governs cancer-relevant alternative splicing decisions, promoting Ras-dependent CD44 variable exon inclusion via interaction with Sam68 and driving oncogenic isoform programs (including NUMB exon 9) that support proliferation and invasion [PMID:16354706, PMID:bio_10.1101_2025.08.20.671097]. Heterozygous truncating variants in SRRM1 impair neuronal proliferation, migration, and neurite outgrowth, establishing a role in nervous system development [PMID:41145827].","teleology":[{"year":1999,"claim":"Established SRRM1 as a splicing coactivator that bridges ESE-bound activators to the spliceosome, answering how purine-rich enhancers communicate with the core splicing machinery.","evidence":"In vitro splicing with immunodepletion plus reciprocal co-IP of SRm160/300 with U2 snRNP and a Tra2 homolog","pmids":["10339552"],"confidence":"High","gaps":["Did not define which subunit carries the activity","Structural basis of the U2/Tra2 bridging interaction unresolved"]},{"year":2000,"claim":"Identified SRm160 as the functionally critical subunit of the SRm160/300 coactivator, resolving the division of labor within the complex.","evidence":"Specific immunodepletion of SRm300 and rescue of splicing with recombinant SRm160","pmids":["10668804"],"confidence":"High","gaps":["Role of SRm300 in the complex left unclear","No structural data on the heterodimer"]},{"year":2001,"claim":"Generalized SRRM1's coactivator role across diverse SR proteins and ESE sequences and demonstrated in vivo importance, answering whether the bridging function is enhancer-specific.","evidence":"Co-IP of multiple SR proteins with SRm160, randomized-ESE splicing, and RNAi epistasis in C. elegans","pmids":["11747818"],"confidence":"High","gaps":["Direct vs. indirect nature of each SR protein contact not mapped","Did not identify endogenous target transcripts"]},{"year":2002,"claim":"Extended SRRM1 beyond splicing to mRNA 3'-end formation, showing it physically links to CPSF and can uncouple 3'-end processing from splicing.","evidence":"In vitro and in vivo 3'-end cleavage assays with overexpression and co-IP with CPSF","pmids":["11739730"],"confidence":"High","gaps":["CPSF contact surface not defined at this stage","Physiological relevance of pre-mRNA uncoupling unclear"]},{"year":2003,"claim":"Defined the mechanistic and spatial basis of SRRM1 function: 3'-end stimulation is EJC-independent, and discrete domains target it to speckles and the nuclear lamina near mRNA exit sites.","evidence":"Tethered-function and in vitro cleavage assays with EJC assembly, C. elegans RNAi epistasis, and deletion-mutant localization imaging","pmids":["12944400","12624182","12581738"],"confidence":"High","gaps":["PWI domain not yet pinpointed as the active element","How matrix targeting couples to processing unresolved"]},{"year":2004,"claim":"Revealed ATP-regulated dynamics at speckles, distinguishing mobile export-associated SRRM1 complexes from immobile splicing complexes.","evidence":"In vitro FRAP in digitonin-permeabilized cells comparing SRm160, RNPS1, and SRm300 mobility","pmids":["15024032"],"confidence":"Medium","gaps":["Identity of the ATP-dependent release factor unknown","Single-lab novel FRAP system"]},{"year":2005,"claim":"Uncovered a cohesin-associated SRRM1 complex distinct from its splicing complex and localized the 3'-end activity to the PWI domain, broadening its interactome.","evidence":"Immunoaffinity MS, gradient fractionation, co-IP/co-localization, and combinatorial RNAi in C. elegans","pmids":["16159877"],"confidence":"High","gaps":["Functional consequence of SRRM1-cohesin association undefined","Whether the two complexes interconvert is unknown"]},{"year":2006,"claim":"Connected SRRM1 to oncogenic splicing by showing Ras-dependent control of CD44 v5 inclusion via Sam68 and a direct effect on tumor invasiveness.","evidence":"siRNA knockdown, overexpression, co-IP with Sam68, RT-PCR splicing, and invasion assays","pmids":["16354706"],"confidence":"High","gaps":["Mechanism linking Ras signaling to SRRM1 activity not defined","Breadth of Sam68-dependent targets unknown"]},{"year":2014,"claim":"Identified post-translational regulation of SRRM1 by LAMMER kinase DOA, linking phosphorylation to its activity in development and sex determination.","evidence":"In vitro kinase assay and Doa-allele genetic epistasis in Drosophila with embryonic localization imaging","pmids":["24907259"],"confidence":"Medium","gaps":["Phosphosites on SRRM1 not mapped","Human kinase ortholog not tested"]},{"year":2017,"claim":"Showed an in vivo splicing-dependent role for SRRM1 in regulating period transcript levels and circadian rhythms in pacemaker neurons.","evidence":"Tissue-specific RNAi and spliced-vs-unspliced per rescue with behavioral assays in Drosophila","pmids":["28801530"],"confidence":"Medium","gaps":["Direct binding to per pre-mRNA not shown","Conservation in mammalian clock not tested"]},{"year":2019,"claim":"Defined the RNA-binding preference of SRRM1 for exonic GCA/AAC repeats and linked sex-specific binding to alternative splicing of transformer.","evidence":"HITS-CLIP in Drosophila sex-specific cell lines with gel-shift and minigene validation","pmids":["29750417"],"confidence":"Medium","gaps":["Human RNA-binding map not established","Structural basis of repeat recognition unknown"]},{"year":2025,"claim":"Positioned SRRM1 as a driver of an oncogenic splicing program shared with SRSF11, controlling NUMB exon 9 and other cancer targets to support proliferation and invasion.","evidence":"Genome-wide CRISPR screen with NUMB splicing reporter, knockdown, proteomics, RNA-seq, and proliferation/invasion assays in colorectal and lung cancer cells (preprint)","pmids":["bio_10.1101_2025.08.20.671097"],"confidence":"Medium","gaps":["Direct vs. indirect target effects not fully separated","Preprint, single lab"]},{"year":2025,"claim":"Implicated SRRM1 in nervous system development through truncating variants that impair neuronal phenotypes in cells and flies.","evidence":"CRISPR-engineered truncating variants in neuronal cells plus Drosophila neuronal RNAi with viability and locomotion readouts","pmids":["41145827"],"confidence":"Medium","gaps":["Splicing targets underlying the neuronal phenotype not defined","Human Mendelian disease classification not established in this entry"]},{"year":2025,"claim":"Suggested SRRM1 is a phosphorylation target of the speckle kinase TAOK2 governing speckle integrity and SR protein-driven splicing.","evidence":"Phosphoproteomics after TAOK2 knockdown with speckle imaging and splicing readouts (preprint)","pmids":["bio_10.1101_2025.09.29.679379"],"confidence":"Low","gaps":["Direct kinase assay on SRRM1 not reported","Preprint, single lab"]},{"year":null,"claim":"How the distinct SRRM1 complexes (splicing, 3'-end processing, cohesin-associated) are partitioned and regulated in human cells, and what signaling controls its switch between normal and oncogenic splicing programs, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No human structural model of SRRM1 complexes","Regulatory inputs governing complex choice unknown","Genome-wide human RNA target map incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[12]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[5,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,5,10]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,3,9]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,13]}],"complexes":["SRm160/300 splicing coactivator","cohesin (SMC1alpha/SMC3/RAD21/SA2)-associated complex"],"partners":["SRRM2","RNPS1","CPSF","SAM68","TLS/FUS","SRSF11","TRA2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IYB3","full_name":"Serine/arginine repetitive matrix protein 1","aliases":["SR-related nuclear matrix protein of 160 kDa","SRm160","Ser/Arg-related nuclear matrix protein"],"length_aa":904,"mass_kda":102.3,"function":"Part of pre- and post-splicing multiprotein mRNP complexes. As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable). Involved in numerous pre-mRNA processing events. Promotes constitutive and exonic splicing enhancer (ESE)-dependent splicing activation by bridging together sequence-specific (SR family proteins, SFRS4, SFRS5 and TRA2B/SFRS10) and basal snRNP (SNRP70 and SNRPA1) factors of the spliceosome. Stimulates mRNA 3'-end cleavage independently of the formation of an exon junction complex. Binds both pre-mRNA and spliced mRNA 20-25 nt upstream of exon-exon junctions. Binds RNA and DNA with low sequence specificity and has similar preference for either double- or single-stranded nucleic acid substrates","subcellular_location":"Nucleus matrix; Nucleus speckle","url":"https://www.uniprot.org/uniprotkb/Q8IYB3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SRRM1","classification":"Common Essential","n_dependent_lines":1141,"n_total_lines":1208,"dependency_fraction":0.9445364238410596},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CPSF6","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"RBM42","stoichiometry":0.2},{"gene":"SF3A1","stoichiometry":0.2},{"gene":"SF3B1","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"SNRPB","stoichiometry":0.2},{"gene":"SNRPB2","stoichiometry":0.2},{"gene":"SNRPC","stoichiometry":0.2},{"gene":"SNRPF","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SRRM1","total_profiled":1310},"omim":[{"mim_id":"615452","title":"PROSTATE CANCER-ASSOCIATED NONCODING RNA 1; PRNCR1","url":"https://www.omim.org/entry/615452"},{"mim_id":"612427","title":"RNA-BINDING MOTIF PROTEIN 25; RBM25","url":"https://www.omim.org/entry/612427"},{"mim_id":"605975","title":"SERINE/ARGININE REPETITIVE MATRIX PROTEIN 1; SRRM1","url":"https://www.omim.org/entry/605975"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nuclear speckles","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SRRM1"},"hgnc":{"alias_symbol":["SRM160","POP101","MGC39488"],"prev_symbol":[]},"alphafold":{"accession":"Q8IYB3","domains":[{"cath_id":"1.20.1390.10","chopping":"19-119","consensus_level":"high","plddt":83.2034,"start":19,"end":119},{"cath_id":"1.20.5","chopping":"122-161","consensus_level":"medium","plddt":80.0807,"start":122,"end":161}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYB3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYB3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYB3-F1-predicted_aligned_error_v6.png","plddt_mean":51.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRRM1","jax_strain_url":"https://www.jax.org/strain/search?query=SRRM1"},"sequence":{"accession":"Q8IYB3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IYB3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IYB3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYB3"}},"corpus_meta":[{"pmid":"16354706","id":"PMC_16354706","title":"Regulation of CD44 alternative splicing by SRm160 and its potential role in tumor cell invasion.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16354706","citation_count":166,"is_preprint":false},{"pmid":"10668804","id":"PMC_10668804","title":"The SRm160/300 splicing coactivator subunits.","date":"2000","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/10668804","citation_count":98,"is_preprint":false},{"pmid":"12581738","id":"PMC_12581738","title":"Proto-oncoprotein TLS/FUS is associated to the nuclear matrix and complexed with splicing factors PTB, SRm160, and SR proteins.","date":"2003","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/12581738","citation_count":88,"is_preprint":false},{"pmid":"11739730","id":"PMC_11739730","title":"SRm160 splicing coactivator promotes transcript 3'-end cleavage.","date":"2002","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11739730","citation_count":86,"is_preprint":false},{"pmid":"10339552","id":"PMC_10339552","title":"The SRm160/300 splicing coactivator is required for exon-enhancer function.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10339552","citation_count":72,"is_preprint":false},{"pmid":"12624182","id":"PMC_12624182","title":"The spatial targeting and nuclear matrix binding domains of SRm160.","date":"2003","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12624182","citation_count":56,"is_preprint":false},{"pmid":"11747818","id":"PMC_11747818","title":"Multiple interactions between SRm160 and SR family proteins in enhancer-dependent splicing and development of C. elegans.","date":"2001","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/11747818","citation_count":38,"is_preprint":false},{"pmid":"12944400","id":"PMC_12944400","title":"An evolutionarily conserved role for SRm160 in 3'-end processing that functions independently of exon junction complex formation.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12944400","citation_count":38,"is_preprint":false},{"pmid":"16159877","id":"PMC_16159877","title":"Proteomic analysis of SRm160-containing complexes reveals a conserved association with cohesin.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16159877","citation_count":29,"is_preprint":false},{"pmid":"15024032","id":"PMC_15024032","title":"In vitro FRAP reveals the ATP-dependent nuclear mobilization of the exon junction complex protein SRm160.","date":"2004","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15024032","citation_count":28,"is_preprint":false},{"pmid":"36270072","id":"PMC_36270072","title":"SRRM1 promotes the proliferation, migration, and invasion of hepatocellular carcinoma cells by regulating the JAK/STAT signaling pathway.","date":"2022","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/36270072","citation_count":16,"is_preprint":false},{"pmid":"36518527","id":"PMC_36518527","title":"A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1.","date":"2022","source":"NAR cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36518527","citation_count":12,"is_preprint":false},{"pmid":"24907259","id":"PMC_24907259","title":"Multifunctional RNA processing protein SRm160 induces apoptosis and regulates eye and genital development in Drosophila.","date":"2014","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24907259","citation_count":9,"is_preprint":false},{"pmid":"28801530","id":"PMC_28801530","title":"Rhythmic Behavior Is Controlled by the SRm160 Splicing Factor in Drosophila melanogaster.","date":"2017","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28801530","citation_count":7,"is_preprint":false},{"pmid":"29750417","id":"PMC_29750417","title":"HITS-CLIP reveals sex-differential RNA binding and alterative splicing regulation of SRm160 in Drosophila.","date":"2019","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29750417","citation_count":6,"is_preprint":false},{"pmid":"40729735","id":"PMC_40729735","title":"A Prion-Like Domain in EBV EBNA1 Promotes Phase Separation and Enables SRRM1 Splicing.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40729735","citation_count":3,"is_preprint":false},{"pmid":"41145827","id":"PMC_41145827","title":"Heterozygous loss of SRRM1 may be associated with neurodevelopmental phenotypes and anomalies in cell growth and neurite morphology.","date":"2025","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/41145827","citation_count":1,"is_preprint":false},{"pmid":"39758250","id":"PMC_39758250","title":"Clinical value of circulating splicing factors in prostate cancer: SRRM1 as a novel predictive biomarker and therapeutic target.","date":"2024","source":"Molecular therapy. Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39758250","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.20.671097","title":"SRRM1 coordinates an alternative splicing program that promotes expression of oncogenic protein isoforms","date":"2025-08-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.20.671097","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.29.679379","title":"Coordination of nuclear RNA processing by speckle-localized kinase TAOK2","date":"2025-09-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.29.679379","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11254,"output_tokens":4729,"usd":0.052348,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12763,"output_tokens":4245,"usd":0.08497,"stage2_stop_reason":"end_turn"},"total_usd":0.137318,"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\": 1999,\n      \"finding\": \"SRm160/300 splicing coactivator is required for a purine-rich exonic splicing enhancer (ESE) to promote splicing of a Drosophila doublesex pre-mRNA. SRm160/300 independently interacts with U2 snRNP and with a human homolog of Transformer 2 (which binds purine-rich ESEs), suggesting it bridges ESE-bound activators with the snRNP spliceosome machinery.\",\n      \"method\": \"In vitro splicing assays with immunodepletion, co-immunoprecipitation of SRm160/300 with U2 snRNP and Tra2 homolog\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro splicing reconstitution with depletion, reciprocal co-IP for interactions, replicated across multiple labs\",\n      \"pmids\": [\"10339552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SRm160 is the more critical subunit of the SRm160/300 coactivator for splicing of SRm160/300-dependent pre-mRNAs. Specific depletion of SRm300 does not prevent splicing, whereas addition of recombinant SRm160 alone to SRm160/300-depleted reactions specifically activates splicing.\",\n      \"method\": \"Specific immunodepletion of SRm300 from splicing extracts; rescue with recombinant SRm160; cDNA isolation and sequence analysis of SRm300\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro splicing reconstitution with depletion and recombinant protein rescue, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"10668804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SRm160 functions as a general splicing coactivator by interacting with multiple SR family proteins bound to diverse ESE sequences. Multiple SR family and SR-related proteins co-immunoprecipitate specifically with SRm160 under low-salt conditions. Genetic epistasis in C. elegans shows that simultaneous RNAi of CeSRm160 and any individual CeSR family gene produces unfertilized oocytes, demonstrating critical functional interactions in vivo.\",\n      \"method\": \"Co-immunoprecipitation of SR proteins with SRm160; RNA interference (RNAi) genetic epistasis in C. elegans; in vitro splicing with randomized ESE sequences\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus genetic epistasis in two orthogonal systems, replicated across labs\",\n      \"pmids\": [\"11747818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SRm160 participates in mRNA 3'-end formation: overexpression promotes 3'-end cleavage in vivo and in vitro. At high levels, SRm160 activates 3'-end cleavage and cytoplasmic accumulation of unspliced pre-mRNAs, uncoupling the splicing requirement for 3'-end formation and nuclear export. SRm160 associates specifically with the cleavage polyadenylation specificity factor (CPSF) and stimulates cleavage of splicing-active pre-mRNAs more efficiently than splicing-inactive ones.\",\n      \"method\": \"In vivo overexpression assays; in vitro 3'-end cleavage assays; co-immunoprecipitation of SRm160 with CPSF\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro cleavage assay, co-IP with CPSF, in vivo overexpression with mechanistic readout, multiple orthogonal methods\",\n      \"pmids\": [\"11739730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SRm160 is associated with the nuclear matrix and co-immunoprecipitates with TLS/FUS along with splicing factors PTB (hnRNPI) and SR proteins (SC35, SRp75), suggesting SRm160 participates in spliceosome assembly within the nuclear matrix context.\",\n      \"method\": \"Co-immunoprecipitation from nuclear extracts; co-immunolocalization; splicing assays with TLS/FUS-immunodepleted extracts\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP with coimmunolocalization, single lab, TLS/FUS-focused study\",\n      \"pmids\": [\"12581738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SRm160 contains two contiguous domains (amino acids 300–350 and 351–688) that independently target it to nuclear matrix sites at splicing speckled domains. The N-terminal domain localizes SRm160 to the nuclear lamina near sites where mRNA exits the nucleus. These domains were identified as the spatial targeting and nuclear matrix binding domains.\",\n      \"method\": \"Fluorescence microscopy of FLAG- and EGFP-tagged deletion mutant proteins transfected into cells; nuclear matrix binding assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — systematic deletion mutagenesis with direct subcellular localization imaging, single lab\",\n      \"pmids\": [\"12624182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SRm160 stimulates 3'-end cleavage independently of its association with the exon junction complex (EJC). EJC components RNPS1, REF, UAP56, and Y14 interact with SRm160, but only SRm160 and RNPS1 stimulate 3'-end cleavage when tethered to transcripts. Assembly of an EJC adjacent to the cleavage/polyadenylation signal in vitro did not significantly affect cleavage efficiency. In C. elegans, simultaneous RNAi of SRm160 and cleavage factor CstF-50 caused late embryonic arrest, demonstrating an evolutionarily conserved functional interaction between SRm160 and the 3'-end cleavage machinery.\",\n      \"method\": \"In vitro tethered-function assays; in vitro 3'-end cleavage assays with EJC assembly; RNAi epistasis in C. elegans\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro cleavage reconstitution, tethered-function assays, and genetic epistasis in vivo, multiple orthogonal approaches\",\n      \"pmids\": [\"12944400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SRm160 has ATP-dependent nuclear mobility at splicing speckled domains, revealed by in vitro FRAP in digitonin-permeabilized cells. Both EGFP-labeled and endogenous SRm160 are released from speckle sites by an ATP-dependent mechanism, suggesting SRm160-containing RNA export complexes (but not splicing complexes) have ATP-regulated release. In contrast, SRm300 remains immobile after ATP supplementation.\",\n      \"method\": \"In vitro FRAP (fluorescence recovery after photobleaching) in digitonin-permeabilized cells; comparison of EGFP-SRm160, endogenous SRm160, RNPS1, and SRm300 mobility\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live-cell imaging with functional perturbation (ATP depletion/addition), single lab, novel in vitro FRAP system\",\n      \"pmids\": [\"15024032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SRm160-containing complexes are associated with cohesin subunits SMC1alpha, SMC3, RAD21, and SA2. Gradient fractionation revealed two predominant SRm160 complexes: one enriched in splicing components and another enriched in cohesin subunits. Co-immunoprecipitation, co-localization, and combinatorial RNAi in C. elegans support conserved functional interactions between SRm160 and cohesin. SRm160's N-terminal PWI domain mediates its 3'-end processing stimulatory activity.\",\n      \"method\": \"Immunoaffinity purification + tandem mass spectrometry (gel-free); gradient fractionation; co-immunoprecipitation; co-localization; combinatorial RNAi in C. elegans\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-based interactome plus reciprocal Co-IP plus genetic epistasis in C. elegans, multiple orthogonal methods\",\n      \"pmids\": [\"16159877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SRm160 regulates CD44 alternative splicing in a Ras-dependent manner: overexpression of SRm160 stimulates inclusion of CD44 variable exon 5 (v5) when Ras is activated, while siRNA-mediated silencing of SRm160 reduces v5 inclusion. SRm160 co-immunoprecipitates with Sam68, a protein that also stimulates v5 inclusion in a Ras-dependent manner, indicating these two proteins interact to regulate CD44 splicing. siRNA depletion of SRm160 reduces CD44 isoform levels and decreases tumor cell invasiveness.\",\n      \"method\": \"siRNA knockdown; overexpression; co-immunoprecipitation (SRm160 with Sam68); RT-PCR splicing assays; invasion assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, loss-of-function (siRNA) with defined molecular and cellular phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"16354706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In Drosophila, SRm160 is phosphorylated in vitro by the LAMMER kinase DOA, and DOA kinase alleles suppress overexpression phenotypes of SRm160 in the eye while enhancing genital disc phenotypes, indicating DOA-mediated phosphorylation modifies SRm160 activity. SRm160 overexpression causes apoptosis in the Drosophila eye and is required for somatic sex determination. SRm160 protein is concentrated in nuclei of precellular embryos but is rapidly excluded or degraded upon cellularization.\",\n      \"method\": \"In vitro kinase assay (DOA phosphorylates SRm160); genetic epistasis (Doa alleles modifying SRm160 overexpression/loss-of-function phenotypes); immunofluorescence localization in embryos\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay plus genetic epistasis, single lab, Drosophila model\",\n      \"pmids\": [\"24907259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In Drosophila, SRm160 is required in pacemaker neurons for proper circadian oscillations. Reduced SRm160 in adult pacemaker neurons impairs locomotor circadian rhythms and markedly reduces period (per) mRNA levels. The arrhythmicity is rescued by a fully spliced per construct but not by an extra copy of the endogenous per locus, demonstrating that SRm160 positively regulates per levels in a splicing-dependent manner.\",\n      \"method\": \"Tissue-specific RNAi knockdown in pacemaker neurons; genetic rescue with spliced vs. unspliced per constructs; behavioral assays; neuropeptide immunostaining (PDF/PIGMENT DISPERSING FACTOR)\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with functional rescue experiments, single lab, Drosophila in vivo model\",\n      \"pmids\": [\"28801530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SRm160 preferentially binds to exonic trinucleotide repeats GCA and AAC, as identified by HITS-CLIP in Drosophila sex-specific cell lines (S2 male, Kc female). Binding was validated by in vitro gel-shift assays and in vivo minigene splicing assays. SRm160 regulates alternative splicing of the sex-determination factor transformer, and 492 differential binding sites between male and female cells were identified, enriched for splicing factor transcripts.\",\n      \"method\": \"HITS-CLIP (high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation); in vitro gel-shift assay; minigene splicing assays; fly mutant analysis\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — HITS-CLIP for genome-wide RNA binding plus in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"29750417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SRRM1 promotes an alternative splicing program favoring oncogenic isoforms including NUMB exon 9, identified in a genome-wide CRISPR screen. SRRM1 and SRSF11 share common protein interactors, RNA targets, and oncogenic splicing effects on targets including CD44, MKNK2, ECT2, DIAPH1, KAT5, TCF7L2, FOXM1, and TBX3. Loss of SRRM1 reduces Cyclin D1, Notum, and PRDX2 expression and decreases proliferation, colony formation, and invasion in colorectal and lung cancer cells.\",\n      \"method\": \"Genome-wide CRISPR screen with NUMB exon 9 splicing reporter; siRNA/shRNA knockdown; proteomics for shared interactors; RNA-seq for splicing targets; cell proliferation, colony formation, and invasion assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus mechanistic follow-up with defined splicing targets and cellular phenotypes, preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.08.20.671097\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SRRM1 (and SRRM2) are potential direct phosphorylation targets of the nuclear speckle-localized kinase TAOK2, as revealed by phosphoproteomics. TAOK2 knockdown perturbs nearly all speckle-resident SR-rich proteins while leaving hnRNPs unperturbed, suggesting SRRM1/2 phosphorylation by TAOK2 plays a structural maintenance role at nuclear speckles that impacts SR protein-driven exon inclusion.\",\n      \"method\": \"Phosphoproteomics after siRNA knockdown of TAOK2; siRNA knockdown functional readouts (alternative splicing, export, transcript abundance); nuclear speckle imaging\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3–4 / Weak — phosphoproteomics implicates SRRM1 as a target but direct kinase assay for SRRM1 not reported; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.09.29.679379\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Heterozygous truncating variants in SRRM1 (introduced via CRISPR-Cas9) cause impaired proliferation, migration, and neurite outgrowth in SKNBE2 neuronal cells differentiated in vitro. Pan-neuronal knockdown of Drosophila Srrm1 reduces viability, and motoneuronal knockdown impairs neurological function, establishing a role for SRRM1 in nervous system development.\",\n      \"method\": \"CRISPR-Cas9 introduction of truncating variants; neuronal differentiation assays; cell proliferation, migration, and neurite morphology quantification; Drosophila pan-neuronal and motoneuronal RNAi knockdown with viability and locomotion assays\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR-engineered loss-of-function with defined cellular phenotypes plus orthogonal in vivo Drosophila model, single study\",\n      \"pmids\": [\"41145827\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SRRM1 (SRm160) is a serine/arginine-repeat-related nuclear matrix protein that functions as a general splicing coactivator by bridging ESE-bound SR family proteins with the snRNP spliceosome machinery, promotes mRNA 3'-end cleavage via an interaction with CPSF through its PWI domain (independently of the exon junction complex), associates with cohesin subunits, is released from nuclear speckles by an ATP-dependent mechanism, is phosphorylated by LAMMER/TAOK2-family kinases, and regulates cancer-associated alternative splicing events (including CD44 and NUMB isoforms) that influence cell invasion and oncogenic signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SRRM1 (SRm160) is a nuclear matrix-associated serine/arginine-repeat protein that functions as a general splicing coactivator, bridging exonic splicing enhancer (ESE)-bound SR family activators with the snRNP spliceosome to promote pre-mRNA splicing [#0, #2]. Within the SRm160/300 coactivator it is the catalytically critical subunit, as recombinant SRm160 alone rescues splicing of SRm160/300-dependent pre-mRNAs [#1], and it interacts directly with U2 snRNP and a Tra2 homolog to couple ESE recognition to spliceosome assembly [#0]. Beyond splicing, SRRM1 stimulates mRNA 3'-end cleavage through association with CPSF, an activity mapped to its N-terminal PWI domain and shown to be independent of the exon junction complex [#3, #6, #8]. It localizes to nuclear speckle splicing domains via discrete spatial-targeting and matrix-binding domains and undergoes ATP-dependent release from these sites, consistent with a role in coupling splicing to mRNA export [#5, #7]. SRRM1 additionally partitions into a distinct cohesin-associated complex containing SMC1alpha, SMC3, RAD21, and SA2 [#8]. Functionally, SRRM1 governs cancer-relevant alternative splicing decisions, promoting Ras-dependent CD44 variable exon inclusion via interaction with Sam68 and driving oncogenic isoform programs (including NUMB exon 9) that support proliferation and invasion [#9, #13]. Heterozygous truncating variants in SRRM1 impair neuronal proliferation, migration, and neurite outgrowth, establishing a role in nervous system development [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established SRRM1 as a splicing coactivator that bridges ESE-bound activators to the spliceosome, answering how purine-rich enhancers communicate with the core splicing machinery.\",\n      \"evidence\": \"In vitro splicing with immunodepletion plus reciprocal co-IP of SRm160/300 with U2 snRNP and a Tra2 homolog\",\n      \"pmids\": [\"10339552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which subunit carries the activity\", \"Structural basis of the U2/Tra2 bridging interaction unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified SRm160 as the functionally critical subunit of the SRm160/300 coactivator, resolving the division of labor within the complex.\",\n      \"evidence\": \"Specific immunodepletion of SRm300 and rescue of splicing with recombinant SRm160\",\n      \"pmids\": [\"10668804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of SRm300 in the complex left unclear\", \"No structural data on the heterodimer\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Generalized SRRM1's coactivator role across diverse SR proteins and ESE sequences and demonstrated in vivo importance, answering whether the bridging function is enhancer-specific.\",\n      \"evidence\": \"Co-IP of multiple SR proteins with SRm160, randomized-ESE splicing, and RNAi epistasis in C. elegans\",\n      \"pmids\": [\"11747818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. indirect nature of each SR protein contact not mapped\", \"Did not identify endogenous target transcripts\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Extended SRRM1 beyond splicing to mRNA 3'-end formation, showing it physically links to CPSF and can uncouple 3'-end processing from splicing.\",\n      \"evidence\": \"In vitro and in vivo 3'-end cleavage assays with overexpression and co-IP with CPSF\",\n      \"pmids\": [\"11739730\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CPSF contact surface not defined at this stage\", \"Physiological relevance of pre-mRNA uncoupling unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the mechanistic and spatial basis of SRRM1 function: 3'-end stimulation is EJC-independent, and discrete domains target it to speckles and the nuclear lamina near mRNA exit sites.\",\n      \"evidence\": \"Tethered-function and in vitro cleavage assays with EJC assembly, C. elegans RNAi epistasis, and deletion-mutant localization imaging\",\n      \"pmids\": [\"12944400\", \"12624182\", \"12581738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PWI domain not yet pinpointed as the active element\", \"How matrix targeting couples to processing unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealed ATP-regulated dynamics at speckles, distinguishing mobile export-associated SRRM1 complexes from immobile splicing complexes.\",\n      \"evidence\": \"In vitro FRAP in digitonin-permeabilized cells comparing SRm160, RNPS1, and SRm300 mobility\",\n      \"pmids\": [\"15024032\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the ATP-dependent release factor unknown\", \"Single-lab novel FRAP system\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Uncovered a cohesin-associated SRRM1 complex distinct from its splicing complex and localized the 3'-end activity to the PWI domain, broadening its interactome.\",\n      \"evidence\": \"Immunoaffinity MS, gradient fractionation, co-IP/co-localization, and combinatorial RNAi in C. elegans\",\n      \"pmids\": [\"16159877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of SRRM1-cohesin association undefined\", \"Whether the two complexes interconvert is unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected SRRM1 to oncogenic splicing by showing Ras-dependent control of CD44 v5 inclusion via Sam68 and a direct effect on tumor invasiveness.\",\n      \"evidence\": \"siRNA knockdown, overexpression, co-IP with Sam68, RT-PCR splicing, and invasion assays\",\n      \"pmids\": [\"16354706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking Ras signaling to SRRM1 activity not defined\", \"Breadth of Sam68-dependent targets unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified post-translational regulation of SRRM1 by LAMMER kinase DOA, linking phosphorylation to its activity in development and sex determination.\",\n      \"evidence\": \"In vitro kinase assay and Doa-allele genetic epistasis in Drosophila with embryonic localization imaging\",\n      \"pmids\": [\"24907259\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosites on SRRM1 not mapped\", \"Human kinase ortholog not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed an in vivo splicing-dependent role for SRRM1 in regulating period transcript levels and circadian rhythms in pacemaker neurons.\",\n      \"evidence\": \"Tissue-specific RNAi and spliced-vs-unspliced per rescue with behavioral assays in Drosophila\",\n      \"pmids\": [\"28801530\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding to per pre-mRNA not shown\", \"Conservation in mammalian clock not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the RNA-binding preference of SRRM1 for exonic GCA/AAC repeats and linked sex-specific binding to alternative splicing of transformer.\",\n      \"evidence\": \"HITS-CLIP in Drosophila sex-specific cell lines with gel-shift and minigene validation\",\n      \"pmids\": [\"29750417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Human RNA-binding map not established\", \"Structural basis of repeat recognition unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Positioned SRRM1 as a driver of an oncogenic splicing program shared with SRSF11, controlling NUMB exon 9 and other cancer targets to support proliferation and invasion.\",\n      \"evidence\": \"Genome-wide CRISPR screen with NUMB splicing reporter, knockdown, proteomics, RNA-seq, and proliferation/invasion assays in colorectal and lung cancer cells (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.08.20.671097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect target effects not fully separated\", \"Preprint, single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated SRRM1 in nervous system development through truncating variants that impair neuronal phenotypes in cells and flies.\",\n      \"evidence\": \"CRISPR-engineered truncating variants in neuronal cells plus Drosophila neuronal RNAi with viability and locomotion readouts\",\n      \"pmids\": [\"41145827\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Splicing targets underlying the neuronal phenotype not defined\", \"Human Mendelian disease classification not established in this entry\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Suggested SRRM1 is a phosphorylation target of the speckle kinase TAOK2 governing speckle integrity and SR protein-driven splicing.\",\n      \"evidence\": \"Phosphoproteomics after TAOK2 knockdown with speckle imaging and splicing readouts (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.09.29.679379\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct kinase assay on SRRM1 not reported\", \"Preprint, single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct SRRM1 complexes (splicing, 3'-end processing, cohesin-associated) are partitioned and regulated in human cells, and what signaling controls its switch between normal and oncogenic splicing programs, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No human structural model of SRRM1 complexes\", \"Regulatory inputs governing complex choice unknown\", \"Genome-wide human RNA target map incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 5, 10]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 3, 9]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 13]}\n    ],\n    \"complexes\": [\n      \"SRm160/300 splicing coactivator\",\n      \"cohesin (SMC1alpha/SMC3/RAD21/SA2)-associated complex\"\n    ],\n    \"partners\": [\n      \"SRRM2\",\n      \"RNPS1\",\n      \"CPSF\",\n      \"Sam68\",\n      \"TLS/FUS\",\n      \"SRSF11\",\n      \"Tra2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}