{"gene":"SRRM2","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":2000,"finding":"SRRM2 (termed SRL300) was cloned and characterized as a novel RNA-binding protein containing a unique RNA-binding region and two large RS (arginine-serine repeat) domains with multiple phosphorylation sites, expressed in both human and rat cells.","method":"cDNA cloning and characterization; protein detection by immunoblot","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 — direct cloning and biochemical identification, single lab","pmids":["11004489"],"is_preprint":false},{"year":2002,"finding":"SRRM2 (SRm300) was identified as a component of catalytically active spliceosomal C complexes containing splicing intermediates, detected by tandem mass spectrometry in affinity-purified native spliceosomes.","method":"Affinity purification of native spliceosomes followed by tandem mass spectrometry","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 — direct biochemical identification in purified complexes, single study","pmids":["11991638"],"is_preprint":false},{"year":2003,"finding":"SRRM2 (SRm300) physically interacts with Pinin (Pnn/DRS/memA) via Pnn's polyserine/RS motif and co-localizes with Pnn and SRp75 in nuclear speckles in corneal epithelial cells; these proteins co-immunoprecipitate and form a multiprotein complex associated with pre-mRNA splicing machinery.","method":"Yeast two-hybrid, co-immunoprecipitation, co-transfection with immunostaining in HCE-T and HEK-293 cells","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal co-IP and Y2H with domain mapping, single lab","pmids":["14578391"],"is_preprint":false},{"year":2003,"finding":"SRRM2 (TAXREB803/SRL300) functions as a transcriptional co-activator for HTLV-1 Tax protein; it binds to the Tax responsive element (TxRE) in a GC-rich sequence-dependent manner, enhances Tax-dependent transcription and CREB binding to TxRE, and physically interacts with Tax as shown by co-immunoprecipitation. Knockdown of endogenous SRRM2 by siRNA dramatically reduces Tax transactivation of the HTLV-1 LTR.","method":"Yeast two-hybrid, co-immunoprecipitation, indirect immunofluorescence, siRNA knockdown with luciferase reporter assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP plus functional siRNA knockdown with defined transcriptional readout, single lab","pmids":["12941912"],"is_preprint":false},{"year":2009,"finding":"Yeast Cwc21p (ortholog of human SRm300/SRRM2) binds directly to the splicing factors Prp8p and Snu114p, docking it to U5 snRNP proteins, and is the first NTC-related protein known to interact directly with U5 snRNP. The conserved cwf21 domain in Cwc21p is identified as the Prp8p binding site by chemical cross-linking. Genetic interactions with Isy1p place Cwc21p at or prior to the first catalytic step of splicing. Importantly, human SRm300 was shown to be a functional ortholog of Cwc21p, also interacting directly with Prp8p and Snu114p, placing SRRM2 at the catalytic center of the human spliceosome.","method":"Direct binding assays, chemical cross-linking, yeast two-hybrid, genetic epistasis, proteomic techniques including tandem affinity purification","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1–2 — direct biochemical binding assays, cross-linking, genetic epistasis, and functional ortholog validation across species","pmids":["19854871"],"is_preprint":false},{"year":2009,"finding":"Cwc21 (yeast ortholog of SRm300/SRRM2) shows strong genetic, physical, and functional interactions with Isy1 (a protein implicated in the first catalytic step of splicing and splicing fidelity), and genetic interaction mapping supports multiple roles for Cwc21/SRm300 in the formation and function of splicing complexes including activation of splicing.","method":"Quantitative genetic interaction mapping (E-MAP), mass spectrometry of tandem affinity-purified complexes, microarray profiling","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (genetic interaction mapping, proteomics, functional assays), replicated across two independent studies (19854871 and 19789211)","pmids":["19789211","19854871"],"is_preprint":false},{"year":2013,"finding":"RSR-2 (C. elegans ortholog of SRRM2) is essential for viability and lies within the germline sex determination pathway by genetic epistasis. RSR-2 co-precipitates with chromatin and co-localizes with RNA Polymerase II (RNAPII) in germline nuclei, with a ChIP-Seq profile mirroring that of RNAPII. RSR-2 interacts with RNAPII and affects RNAPII phosphorylation states in a splicing-independent manner, and its strongest proteomic interactors are PRP-8 and PRP-19. This reveals a transcriptional function for SRRM2/RSR-2 beyond splicing.","method":"RNAi/mutant genetic epistasis, ChIP-Seq, co-immunoprecipitation, quantitative proteomics (mass spectrometry), immunostaining","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (genetic epistasis, ChIP-Seq, Co-IP, proteomics) in a single study with functional consequences","pmids":["23754964"],"is_preprint":false},{"year":2015,"finding":"A germline missense mutation in SRRM2 (S346F) co-segregates with papillary thyroid carcinoma and causes significant differences in alternative splicing affecting 1,642 exons in leukocytes from mutation carriers, with a net higher ratio of exon inclusion, establishing that SRRM2 S346F alters alternative splicing of downstream target genes.","method":"Whole exome sequencing, haplotype analysis, RNA-Seq comparison of mutation carriers vs. controls, RT-PCR validation of 7 exons","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — RNA-Seq with experimental validation of splicing changes linked to a defined SRRM2 mutation, single lab","pmids":["26135620"],"is_preprint":false},{"year":2017,"finding":"Human cactin physically and functionally interacts with SRRM2 (and DHX8); cactin depletion leads to premature sister chromatid separation and genome instability caused by incomplete splicing of the sororin (CDCA5) pre-mRNA, establishing that cellular complexes comprising cactin, DHX8, and SRRM2 sustain pre-mRNA splicing fidelity for specific targets required for chromosome segregation.","method":"Co-immunoprecipitation, siRNA knockdown with defined phenotypic readouts (chromosome separation, genome instability), RNA-Seq splicing analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with functional knockdown and mechanistic splicing analysis, single lab","pmids":["28062851"],"is_preprint":false},{"year":2020,"finding":"The SC35 monoclonal antibody (widely used to mark nuclear speckles) was found to primarily target SRRM2, not SRSF2/SC35 as previously believed. Co-depletion of SON and SRRM2, or depletion of SON in cells where the intrinsically disordered regions (IDRs) of SRRM2 are genetically deleted, leads to near-complete dissolution of nuclear speckles, establishing SON and SRRM2 as the core scaffold proteins required for nuclear speckle formation.","method":"Antibody characterization (immunoprecipitation-MS), siRNA co-depletion, CRISPR-mediated genetic deletion of SRRM2 IDRs, fluorescence microscopy of nuclear speckles","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including genetic deletion, co-depletion, and MS-based antibody characterization; replicated findings","pmids":["33095160"],"is_preprint":false},{"year":2022,"finding":"SRRM2 forms biomolecular condensates via liquid-liquid phase separation (LLPS), displaying spherical shape, dynamic rearrangement, coalescence, and concentration-dependent behavior confirmed by in vitro experiments. SRRM2 organizes nuclear speckles throughout the cell cycle. SRRM2 deficiency causes skipping of cassette exons with short introns and weak splice sites, and in THP-1 cells compromises viability, upregulates differentiation markers, and sensitizes cells to anti-leukemia drugs. SRRM2 regulates FES and MUC1 splice isoforms linked to innate immunity and oncogenic properties.","method":"EGFP-SRRM2 knock-in HEK293T cells, live-cell imaging, in vitro phase separation assays, RNA-Seq after SRRM2 depletion, cell viability assays, flow cytometry","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — endogenous tagging, live-cell imaging, in vitro LLPS validation, and RNA-Seq with functional cellular readouts; multiple orthogonal methods","pmids":["35929045"],"is_preprint":false},{"year":2023,"finding":"Nuclear arginyl-tRNA synthetase (ArgRS) physically interacts and co-localizes with SRRM2; during inflammation, arginine depletion reduces nuclear ArgRS levels, which correlates with changes in condensate-like nuclear trafficking of SRRM2 and altered splice-site usage in specific genes, resulting in different protein isoforms that alter cellular metabolism and peptide presentation to immune cells.","method":"Co-immunoprecipitation, co-localization imaging, siRNA depletion, RNA-Seq splice-site analysis, metabolic and immunopeptidome assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, co-localization, and functional RNA-Seq with downstream metabolic/immune readouts; multiple orthogonal methods in a single rigorous study","pmids":["37059883"],"is_preprint":false},{"year":2024,"finding":"SRRM2 and SON form immiscible multiphases within nuclear speckles and are functionally independent, each regulating distinct subsets of alternative splicing targets. SRRM2 forms multicomponent liquid phases through homotypic interaction and heterotypic protein-RNA complex coacervation-driven phase separation. The serine/arginine-rich (RS) domains of SRRM2 form higher-order oligomers required for phase separation, and the serine residues within RS domains fine-tune nuclear speckle liquidity. RS domains can be functionally replaced by synthetic oligomerizable modules.","method":"Live-cell imaging, FRAP, in vitro phase separation assays, RS domain mutagenesis and synthetic module replacement, RNA-Seq of SRRM2 and SON individual knockdowns","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro reconstitution of phase separation, domain mutagenesis, live-cell imaging, and functional RNA-Seq; multiple orthogonal methods","pmids":["38381607"],"is_preprint":false},{"year":2024,"finding":"SRRM2 modulates Srrm2 dosage is critical for maintaining embryonic stem cell pluripotency; Srrm2 heterozygosity in mouse ESCs promotes loss of stemness with coexistence of naive and formative pluripotency markers. The earliest effects are specific alternative splicing changes on a small number of genes, followed by expression changes in metabolism and differentiation-related genes including SRF-regulated targets.","method":"Srrm2 heterozygous mouse ESC model, RNAi knockdown, RNA-Seq, splicing analysis, pluripotency marker immunostaining","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 — genetic model with RNA-Seq splicing analysis and functional pluripotency readouts, single lab","pmids":["38656788"],"is_preprint":false},{"year":2025,"finding":"SRRM2 modulates the levels of both S6K1 and S6K2 to activate the mTOR-S6K pathway in colorectal cancer cells. Mechanistically, SRRM2 facilitates S6K2 expression by regulating alternative splicing of the S6K2 pre-mRNA, and enhances S6K1 protein stability by regulating the E3 ubiquitin ligase WWP2. SRRM2 knockdown or overexpression modulates CRC cell growth in vitro and in vivo.","method":"siRNA knockdown and overexpression, RNA-Seq splicing analysis, protein stability assays, ubiquitination assays, xenograft mouse models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — multiple mechanistic approaches (splicing analysis, ubiquitination assays, in vivo) but single lab","pmids":["39956864"],"is_preprint":false},{"year":2025,"finding":"A point mutation in SRRM2 (identified in an ALS family) causes loss of a specific protein-protein interaction between SRRM2 and the splicing factor ACIN1, leading to widespread differential gene expression converging on dysregulation of synapse-associated pathways, identifying SRRM2 as a novel ALS risk factor.","method":"Endogenous point mutation knock-in cell line, co-immunoprecipitation, RNA-Seq transcriptome analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — endogenous mutation knock-in with co-IP and transcriptome analysis, single lab, preprint","pmids":["bio_10.1101_2025.09.11.675713"],"is_preprint":true},{"year":2024,"finding":"Srrm2+/- heterozygous mice display large-scale changes in gene expression in neuronal and glial cells, reduction of key postsynaptic proteins including the SynGAP-γ isoform, abnormal splicing and elevated expression of Agap3 (a SynGAP interactor), reduced numbers of oligodendrocytes with decreased myelin-related mRNAs and proteins, and behavioral/EEG abnormalities including reduced sleep spindles phenocopying schizophrenia.","method":"Srrm2+/- mouse model, RNA-Seq in multiple brain regions, proteomics, immunostaining, EEG, behavioral testing","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo genetic model with multi-omics and functional readouts, single lab, preprint","pmids":["bio_10.1101_2024.10.10.617460"],"is_preprint":true},{"year":2025,"finding":"Upon simultaneous dTAG-mediated depletion of SON and SRRM2, specific genomic regions (SWING domains) relocate to the nuclear periphery and acquire repressive histone marks (H3K9me3) with transcriptional downregulation of developmental pathway genes, establishing nuclear speckles (scaffolded by SON and SRRM2) as organizers of active chromatin that oppose nuclear lamina-associated gene repression.","method":"Rapid dTAG-mediated co-depletion of SON and SRRM2, Hi-C/3D genomics, ChIP-Seq (H3K9me3), RNA-Seq, patient-derived cell analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — acute depletion with 3D genomics and ChIP-Seq functional validation, single lab, preprint","pmids":["bio_10.1101_2025.10.01.679801"],"is_preprint":true},{"year":2025,"finding":"SRRM2 (and SRRM1) are identified as potential direct phosphorylation substrates of the nuclear speckle-localized kinase TAOK2 by cellular and biochemical phosphoproteomics; TAOK2 knockdown perturbs nearly all speckle-resident SR proteins and disrupts speckle integrity and speckle-localized splicing, suggesting that TAOK2-mediated phosphorylation of SRRM1/2 plays a structural maintenance role at nuclear speckles.","method":"siRNA knockdown, cellular and biochemical phosphoproteomics, RNA-Seq (alternative splicing analysis), immunofluorescence of speckle-resident proteins","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — phosphoproteomic identification without direct in vitro kinase assay confirmation for SRRM2; preprint, single lab","pmids":["bio_10.1101_2025.09.29.679379"],"is_preprint":true},{"year":2024,"finding":"The intrinsically disordered region (IDR) of SRRM2 is required for enlargement of nuclear speckles in the presence of the HIV capsid, and HIV-induced CPSF6 puncta fuse with nuclear speckles via the IDR of SRRM2.","method":"Genetic manipulation and depletion experiments, live-cell imaging of SRRM2 IDR mutants, HIV infection assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — single depletion/mutant experiment in viral context, preprint, single lab","pmids":["bio_10.1101_2024.10.06.616889"],"is_preprint":true},{"year":2025,"finding":"Downregulation of SRRM2 disrupts nuclear speckle integrity and promotes TDP-43 mislocalization from the nucleus to the cytoplasm and loss of TDP-43 splicing function, linking SRRM2-dependent speckle maintenance to TDP-43 pathology relevant to ALS/FTLD.","method":"APEX2 proximity labeling, mass spectrometry interactome, siRNA knockdown of SRRM2, TDP-43 localization imaging, cryptic exon splicing assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — proximity labeling with functional validation by knockdown and splicing assay, single lab, preprint","pmids":["bio_10.1101_2025.04.07.646890"],"is_preprint":true},{"year":2024,"finding":"In senescent cells, SRRM2 is repurposed to cluster CTCF into senescence-induced clusters (SICCs) on nuclear speckles, a process dependent on SRRM2's RNA-binding domain. This CTCF clustering rewires chromatin positioning and is functionally required to sustain the senescence-specific alternative splicing program, as SICC disruption fully reverts alternative splicing patterns.","method":"Super-resolution imaging, 3D genomics, functional splicing assays, SRRM2 domain deletion experiments, siRNA knockdown with chromatin and splicing readouts","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — domain-deletion experiments with functional chromatin and splicing readouts, multiple methods, single lab, preprint","pmids":["bio_10.1101_2024.07.16.603680"],"is_preprint":true},{"year":2025,"finding":"Polyphosphate (polyP) directly interacts with the nuclear speckle core component SRRM2; polyP depletion disrupts nuclear speckle organization and releases splicing factors into the nucleoplasm. PolyP acts as a physiological inhibitor of CLK3 kinase, preventing CLK3-mediated phosphorylation of SR proteins and thereby maintaining nuclear speckle stability. PolyP depletion increases exon inclusion particularly in long multi-exon genes.","method":"BAR (Biotinylation by Antibody Recognition) proximity labeling, polyP depletion, RNA-Seq splicing analysis, CLK3 kinase inhibition assays, nuclear speckle imaging","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — proximity labeling identifies interaction but direct biochemical validation of polyP-SRRM2 binding is limited; preprint, single lab","pmids":["bio_10.1101_2025.01.15.633116"],"is_preprint":true}],"current_model":"SRRM2 is a large serine/arginine-repeat spliceosome-associated scaffold protein that, together with SON, forms the core of nuclear speckles through liquid-liquid phase separation driven by its RS domains and intrinsically disordered regions; at the spliceosome it docks to Prp8 and Snu114 at the catalytic center (via the conserved cwf21 domain) to promote pre-mRNA splicing, regulates alternative splicing of specific exon subsets, interacts with multiple nuclear partners including Pinin, cactin/DHX8, arginyl-tRNA synthetase, and ACIN1, and its RS domain phosphorylation state (regulated by kinases including CLK3/TAOK2) controls nuclear speckle dynamics and splicing activity; beyond splicing, SRRM2 influences RNAPII phosphorylation states, controls S6K1/S6K2 levels via splicing and ubiquitin pathway regulation, and maintains nuclear speckle integrity required for TDP-43 nuclear function and chromatin organization at SWING domains."},"narrative":{"teleology":[{"year":2000,"claim":"Identification of SRRM2 as a novel RS-domain-containing RNA-binding protein established the molecular framework for subsequent studies of its dual roles in splicing and nuclear organization.","evidence":"cDNA cloning and immunoblot characterization of human and rat SRL300/SRRM2","pmids":["11004489"],"confidence":"Medium","gaps":["No functional assays performed","Phosphorylation sites identified but kinase/substrate relationships unknown"]},{"year":2002,"claim":"Detection of SRRM2 in catalytically active spliceosomal C complexes placed it directly within the splicing machinery rather than being solely a nuclear speckle structural component.","evidence":"Affinity purification of native spliceosomes with tandem mass spectrometry identification","pmids":["11991638"],"confidence":"Medium","gaps":["No direct binding partners within the spliceosome mapped","Functional requirement not tested by depletion"]},{"year":2003,"claim":"Mapping the physical interaction between SRRM2 and Pinin at nuclear speckles, and demonstrating a role as a HTLV-1 Tax transcriptional co-activator, revealed that SRRM2 participates in both splicing-associated complexes and transcriptional regulation.","evidence":"Yeast two-hybrid, reciprocal co-IP, siRNA knockdown with luciferase reporter assays in HEK-293 and HCE-T cells","pmids":["14578391","12941912"],"confidence":"Medium","gaps":["Tax co-activation mechanism not resolved at the structural level","Pinin interaction domain on SRRM2 not precisely mapped"]},{"year":2009,"claim":"Biochemical and genetic studies in yeast and human cells established that SRRM2's conserved cwf21 domain docks directly to Prp8 and Snu114 at the catalytic center, positioning SRRM2 at the first step of splicing.","evidence":"Direct binding assays, chemical cross-linking, yeast genetic epistasis, and human ortholog validation","pmids":["19854871","19789211"],"confidence":"High","gaps":["No high-resolution structural data of the cwf21–Prp8 interface","Catalytic contribution versus structural scaffolding role not distinguished"]},{"year":2013,"claim":"Characterization of the C. elegans ortholog RSR-2 revealed a splicing-independent function in modulating RNA polymerase II phosphorylation, broadening SRRM2's role to transcription regulation.","evidence":"ChIP-Seq, co-IP with RNAPII, quantitative proteomics, and genetic epistasis in C. elegans germline","pmids":["23754964"],"confidence":"High","gaps":["Whether RNAPII phosphorylation modulation is conserved in mammals remains untested in this study","Kinase or phosphatase intermediary not identified"]},{"year":2015,"claim":"A germline SRRM2 missense mutation (S346F) co-segregating with papillary thyroid carcinoma was shown to cause widespread alternative splicing changes, providing the first genetic evidence that SRRM2 variants alter splicing of specific exon subsets in human disease.","evidence":"Whole-exome sequencing, RNA-Seq with RT-PCR validation in carrier leukocytes","pmids":["26135620"],"confidence":"Medium","gaps":["Causal mechanism linking S346F to splicing dysregulation not determined","No functional rescue experiment performed"]},{"year":2017,"claim":"Discovery that cactin/DHX8/SRRM2 complexes are required for faithful splicing of the sororin pre-mRNA linked SRRM2 splicing function to genome stability and chromosome segregation.","evidence":"Co-IP, siRNA depletion with chromosome segregation phenotyping, RNA-Seq splicing analysis","pmids":["28062851"],"confidence":"Medium","gaps":["Stoichiometry and assembly order of the cactin–DHX8–SRRM2 complex unknown","Whether SRRM2 is required for all cactin-dependent splicing events untested"]},{"year":2020,"claim":"Demonstration that the SC35 antibody targets SRRM2 (not SRSF2) and that co-depletion of SRRM2 and SON dissolves nuclear speckles established these two proteins as the essential scaffolds of nuclear speckle architecture.","evidence":"IP-MS antibody characterization, siRNA co-depletion, CRISPR deletion of SRRM2 IDRs, fluorescence microscopy","pmids":["33095160"],"confidence":"High","gaps":["Relative contribution of SRRM2 versus SON to speckle nucleation not resolved","Whether speckle dissolution fully explains splicing changes upon depletion unclear"]},{"year":2022,"claim":"In vitro reconstitution and endogenous tagging showed SRRM2 undergoes bona fide liquid-liquid phase separation that organizes nuclear speckles throughout the cell cycle, while RNA-Seq defined its preferred substrates as cassette exons with weak splice sites.","evidence":"EGFP knock-in live-cell imaging, in vitro LLPS assays, RNA-Seq after depletion, cell viability assays in THP-1 cells","pmids":["35929045"],"confidence":"High","gaps":["Molecular determinants distinguishing SRRM2-regulated from SON-regulated exons not fully defined","Phase separation parameters under physiological crowding conditions not measured"]},{"year":2023,"claim":"The interaction between nuclear arginyl-tRNA synthetase and SRRM2 revealed a metabolic sensing axis where arginine depletion during inflammation alters SRRM2 condensate dynamics and splice-site selection, coupling amino acid metabolism to immune-relevant splicing.","evidence":"Reciprocal co-IP, co-localization imaging, RNA-Seq splice-site analysis, immunopeptidome and metabolic assays","pmids":["37059883"],"confidence":"High","gaps":["Direct biochemical mechanism by which ArgRS modulates SRRM2 phase behavior unknown","Whether other aminoacyl-tRNA synthetases regulate speckle components untested"]},{"year":2024,"claim":"Dissection of SRRM2 and SON as forming immiscible multiphases within speckles, with RS domain oligomerization driving SRRM2 phase separation and serine residues tuning liquidity, provided a molecular mechanism for speckle subcompartmentalization and demonstrated functional independence of the two scaffolds in splicing regulation.","evidence":"FRAP, RS domain mutagenesis and synthetic module replacement, in vitro LLPS, individual knockdown RNA-Seq","pmids":["38381607"],"confidence":"High","gaps":["How immiscible SRRM2 and SON phases coordinate during co-transcriptional splicing is unknown","In vivo consequences of synthetic oligomerizable domain replacement not tested in animal models"]},{"year":2024,"claim":"Srrm2 haploinsufficiency in mouse ESCs disrupts the balance between naive and formative pluripotency via specific alternative splicing changes, establishing dosage sensitivity of SRRM2 in cell fate decisions.","evidence":"Srrm2+/- mouse ESC model, RNA-Seq splicing and expression analysis, pluripotency marker immunostaining","pmids":["38656788"],"confidence":"Medium","gaps":["Whether splicing changes are primary cause or secondary consequence of pluripotency loss requires rescue experiments","Human ESC validation not performed"]},{"year":2025,"claim":"SRRM2 was shown to modulate mTOR–S6K signaling in colorectal cancer by regulating S6K2 alternative splicing and S6K1 protein stability via the E3 ligase WWP2, linking its splicing scaffold function to oncogenic signaling.","evidence":"siRNA/overexpression, RNA-Seq splicing analysis, ubiquitination assays, xenograft models","pmids":["39956864"],"confidence":"Medium","gaps":["Whether SRRM2–WWP2 interaction is direct remains unresolved","Generalizability beyond colorectal cancer untested"]},{"year":null,"claim":"Key unresolved questions include the high-resolution structure of SRRM2 within the spliceosome, the precise mechanism by which RS domain phosphorylation (by kinases such as CLK3 and TAOK2) regulates speckle dynamics and splicing target selection, and whether SRRM2 haploinsufficiency underlies neurodevelopmental or neurodegenerative disease in humans.","evidence":"","pmids":[],"confidence":"Low","gaps":["No atomic-resolution structure of SRRM2 in any complex","Kinase–substrate relationships for SRRM2 phosphorylation sites lack direct in vitro validation","Causal role of SRRM2 variants in neuropsychiatric and neurodegenerative disease awaits clinical genetic confirmation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,21]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[9,10,12]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[2,9,10,12]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,6,11]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,4,5,7,8,10,12,14]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,6]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[9,12]}],"complexes":["spliceosomal C complex","nuclear speckle (SON/SRRM2 scaffold)","cactin–DHX8–SRRM2 complex"],"partners":["PRP8","SNU114","SON","PNN","ACIN1","DHX8","RARS1","CACTIN"],"other_free_text":[]},"mechanistic_narrative":"SRRM2 is a large, intrinsically disordered serine/arginine-repeat protein that serves as a core scaffold of nuclear speckles and a direct participant in pre-mRNA splicing catalysis. Together with SON, SRRM2 drives nuclear speckle formation through liquid-liquid phase separation mediated by its RS domains, which form higher-order oligomers whose serine phosphorylation state tunes condensate liquidity; co-depletion of both proteins dissolves speckles and repositions associated chromatin to the nuclear periphery with acquisition of repressive marks [PMID:33095160, PMID:38381607]. At the spliceosome, SRRM2 docks via its conserved cwf21 domain to the catalytic-center proteins Prp8 and Snu114, promoting the first step of splicing, and its depletion causes skipping of cassette exons with weak splice sites and short introns, with downstream consequences for pluripotency, innate immunity, mTOR–S6K signaling, and genome stability through sororin splicing [PMID:19854871, PMID:35929045, PMID:28062851, PMID:39956864]. Beyond splicing, the C. elegans ortholog RSR-2 co-localizes with and modulates RNA polymerase II phosphorylation in a splicing-independent manner, and nuclear arginyl-tRNA synthetase interacts with SRRM2 to couple arginine availability to condensate dynamics and splice-site selection during inflammation [PMID:23754964, PMID:37059883]."},"prefetch_data":{"uniprot":{"accession":"Q9UQ35","full_name":"Serine/arginine repetitive matrix protein 2","aliases":["300 kDa nuclear matrix antigen","Serine/arginine-rich splicing factor-related nuclear matrix protein of 300 kDa","SR-related nuclear matrix protein of 300 kDa","Ser/Arg-related nuclear matrix protein of 300 kDa","Splicing coactivator subunit SRm300","Tax-responsive enhancer element-binding protein 803","TaxREB803"],"length_aa":2752,"mass_kda":299.6,"function":"Required for pre-mRNA splicing as component of the spliceosome. As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable)","subcellular_location":"Nucleus; Nucleus speckle","url":"https://www.uniprot.org/uniprotkb/Q9UQ35/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SRRM2","classification":"Common Essential","n_dependent_lines":567,"n_total_lines":1208,"dependency_fraction":0.4693708609271523},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"SF3A1","stoichiometry":0.2},{"gene":"SF3B1","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"SNRPB","stoichiometry":0.2},{"gene":"SNRPC","stoichiometry":0.2},{"gene":"SNRPF","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SRRM2","total_profiled":1310},"omim":[{"mim_id":"621383","title":"SERINE/ARGININE REPETITIVE MATRIX PROTEIN 3; SRRM3","url":"https://www.omim.org/entry/621383"},{"mim_id":"620439","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 72; MRD72","url":"https://www.omim.org/entry/620439"},{"mim_id":"618536","title":"CACTIN, SPLICEOSOME C COMPLEX SUBUNIT; 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are genetically deleted, leads to near-complete dissolution of nuclear speckles. The SC35 monoclonal antibody, widely used as a nuclear speckle marker, was shown to primarily target SRRM2, not SRSF2.\",\n      \"method\": \"siRNA co-depletion, CRISPR deletion of SRRM2 IDRs, immunofluorescence, antibody epitope mapping\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal genetic perturbations (single vs. double depletions, IDR deletions) with defined structural phenotype, single rigorous study\",\n      \"pmids\": [\"33095160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SRRM2 forms biomolecular condensates with hallmarks of liquid-liquid phase separation (spherical shape, dynamic rearrangement, coalescence, concentration dependence) in cells and in vitro, organizes nuclear speckles throughout the cell cycle, and as a spliceosome component promotes inclusion of cassette exons with short introns and weak splice sites.\",\n      \"method\": \"EGFP-SRRM2 knock-in live-cell imaging, in vitro phase separation assays, RNA-seq after SRRM2 depletion, siRNA knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted in vitro phase separation, live-cell imaging, and transcriptome-wide splicing analysis with multiple orthogonal methods\",\n      \"pmids\": [\"35929045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SRRM2 and SON form immiscible, functionally independent subcompartments within nuclear speckles. SRRM2 drives nuclear speckle subcompartmentalization through homotypic interactions via its serine/arginine-rich (RS) domains forming higher-order oligomers, and heterotypic protein-RNA complex coacervation-driven phase separation. The serine residues within RS domains fine-tune condensate liquidity.\",\n      \"method\": \"Live-cell imaging, in vitro reconstitution of phase separation, mutagenesis of RS domains, synthetic oligomerizable module replacement, RNA-seq\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution, mutagenesis, and live imaging with multiple orthogonal methods in one study\",\n      \"pmids\": [\"38381607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Yeast Cwc21p (ortholog of human SRm300/SRRM2) binds directly to the core spliceosomal proteins Prp8p (via the N-terminal SCwid domain) and Snu114p (via Cwc21p's C-terminus). The conserved cwf21 domain of Cwc21p was identified as the Prp8p binding site by chemical cross-linking. Human SRm300 similarly interacts directly with Prp8p and Snu114p, demonstrating conservation of function at the catalytic center of the spliceosome.\",\n      \"method\": \"Yeast two-hybrid, direct binding assays, chemical cross-linking, proteomic domain mapping, functional complementation\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding assays, cross-linking, and mutagenesis with functional validation across species\",\n      \"pmids\": [\"19854871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Yeast Cwc21p (ortholog of human SRm300/SRRM2) physically associates with the NineTeen Complex (NTC) and functionally interacts with Isy1 at or prior to the first catalytic step of splicing; genetic interaction mapping and mass spectrometry of TAP-purified complexes support roles for Cwc21/SRm300 in spliceosome activation.\",\n      \"method\": \"Quantitative genetic interaction mapping, mass spectrometry of TAP-purified complexes, microarray profiling\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetic, proteomic, transcriptomic) in one study\",\n      \"pmids\": [\"19789211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"C. elegans RSR-2 (ortholog of SRRM2) co-precipitates with chromatin and RNA Polymerase II (RNAPII), affects RNAPII phosphorylation states, and its recruitment to chromatin is splicing-independent, indicating a novel transcription-related function. RSR-2 also interacts with PRP-8 and PRP-19 spliceosomal proteins.\",\n      \"method\": \"ChIP-seq, co-immunoprecipitation, RNA interference, transcriptome analysis, proteomic analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and ChIP-seq in C. elegans ortholog, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23754964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SRRM2 (SRm300) interacts with the cell-adhesion/nuclear protein Pinin (Pnn/DRS/memA) via Pinin's C-terminus (polyserine/RS motif), and co-localizes and co-immunoprecipitates with Pinin and SRp75 in nuclear speckles of corneal epithelial cells, suggesting participation in a multiprotein pre-mRNA splicing complex.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, co-immunostaining, domain mapping\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid and Co-IP with localization, replicated with endogenous proteins\",\n      \"pmids\": [\"14578391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nuclear arginyl-tRNA synthetase (ArgRS) directly interacts and co-localizes with SRRM2. During arginine depletion (inflammatory conditions), decreased nuclear ArgRS correlates with changes in SRRM2 condensate-like nuclear trafficking and altered splice-site usage in specific genes, linking amino acid sensing to splicing via SRRM2.\",\n      \"method\": \"Co-immunoprecipitation, co-localization imaging, mass spectrometry, RNA-seq splice-site analysis, arginine depletion experiments\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, co-localization, and functional splicing analysis with multiple orthogonal methods\",\n      \"pmids\": [\"37059883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Human cactin physically and functionally interacts with spliceosome-associated factors DHX8 and SRRM2, and cactin depletion leads to inefficient pre-mRNA splicing of thousands of transcripts including sororin (CDCA5), causing premature sister chromatid separation and genome instability.\",\n      \"method\": \"Co-immunoprecipitation, siRNA depletion, RNA-seq splicing analysis, cell biology assays (cohesion, genome stability)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and functional depletion with defined phenotype, single lab\",\n      \"pmids\": [\"28062851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Pathological tau drives mislocalization of SRRM2 from the neuronal nucleus to cytoplasmic lesions in Alzheimer's disease brain tissue and in tauopathy transgenic mice, with severity correlating with pathological tau deposition, implicating nuclear speckle scaffold disruption in tauopathy.\",\n      \"method\": \"Immunohistochemistry/immunofluorescence of human AD tissue and transgenic mouse brain, subcellular fractionation\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct localization in human tissue and mouse model with functional implication, but no in vitro mechanistic dissection\",\n      \"pmids\": [\"34187600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A germline missense variant in SRRM2 (S346F) found in a papillary thyroid carcinoma family alters alternative splicing activity, causing significant differences in exon inclusion ratios for 1,642 exons in leukocytes from mutation carriers compared to controls.\",\n      \"method\": \"Whole exome sequencing, RNA-seq, RT-PCR validation of specific exons\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human genetic variant linked to splicing changes validated by RNA-seq and RT-PCR, single lab\",\n      \"pmids\": [\"26135620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SRRM2 modulates levels of S6K1 (by regulating stability via the E3 ubiquitin ligase WWP2) and S6K2 (by modulating alternative splicing of S6K2 pre-mRNA), thereby activating the mTOR-S6K pathway and promoting colorectal cancer cell growth in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown, overexpression, alternative splicing analysis, ubiquitination assays, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple mechanistic arms (splicing and protein stability) with functional in vivo validation, single lab\",\n      \"pmids\": [\"39956864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In senescent cells, SRRM2 is repurposed to cluster CTCF into senescence-induced clusters (SICCs) on nuclear speckles; the SRRM2 RNA-binding domain directs CTCF clustering, and disruption of SICCs reverts alternative splicing patterns, linking SRRM2-mediated speckle organization to the senescence splicing program.\",\n      \"method\": \"Functional assays, super-resolution imaging, 3D genomics, SRRM2 domain mutagenesis, siRNA depletion, RNA-seq\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis, imaging, and functional splicing readout, but preprint only\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TAOK2 kinase phosphorylates nuclear speckle scaffolding proteins SRRM2 (and SRRM1) as identified by cellular and biochemical phosphoproteomics; TAOK2 knockdown perturbs SR protein organization at speckles and impacts alternative splicing, suggesting SRRM2 phosphorylation by TAOK2 maintains speckle structural integrity.\",\n      \"method\": \"siRNA knockdown, phosphoproteomics, RNA-seq, nucleocytoplasmic fractionation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — phosphoproteomics identifies SRRM2 as substrate but direct in vitro kinase assay not shown; preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Polyphosphate (polyP) interacts with the NS core component SRRM2, and polyP depletion disrupts nuclear speckle organization, releasing splicing factors; mechanistically, polyP acts as a physiological inhibitor of CLK3 kinase, preventing SR protein phosphorylation and maintaining NS stability.\",\n      \"method\": \"BAR proximity labeling, polyP depletion experiments, RNA-seq, CLK3 kinase inhibition assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — interaction identified by proximity labeling, functional consequence shown but direct polyP-SRRM2 binding not fully reconstituted; preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A point mutation in SRRM2 identified in a familial ALS pedigree causes loss of a specific protein-protein interaction between SRRM2 and the splicing factor ACIN1, and leads to widespread differential gene expression converging on dysregulation of synapse-associated pathways.\",\n      \"method\": \"Endogenous knock-in of ALS point mutation, co-immunoprecipitation (interaction loss), transcriptome analysis (RNA-seq)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP demonstrating loss of interaction and transcriptome analysis; preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Depletion of nuclear speckle core proteins SON and SRRM2 causes specific genomic regions (SWING domains) to relocate to the nuclear periphery, acquire repressive H3K9me3 marks, and undergo transcriptional downregulation, establishing nuclear speckles as organizers of active chromatin opposing repressive compartments.\",\n      \"method\": \"dTAG-mediated rapid degradation of SON and SRRM2, Hi-C/3D genomics, ChIP-seq for histone marks, RNA-seq, patient-derived cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — rapid inducible depletion system with 3D genomics, histone modification, and transcriptional readouts; preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The intrinsically disordered region (IDR) of SRRM2 is required to enlarge nuclear speckles in the presence of the HIV capsid, and SRRM2 participates in the fusion of HIV-induced CPSF6 puncta with nuclear speckles.\",\n      \"method\": \"Genetic manipulation and depletion experiments, live-cell imaging of SRRM2-IDR deletion cells, HIV infection assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — IDR deletion with imaging readout but limited mechanistic dissection; preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Downregulation of SRRM2 promotes TDP-43 mislocalization from the nucleus and loss of splicing function, linking nuclear speckle integrity (via SRRM2) to TDP-43 pathology relevant to ALS/FTLD.\",\n      \"method\": \"siRNA knockdown of SRRM2, TDP-43 localization assays, functional splicing screen\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single knockdown with localization readout, part of a larger screen; preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SRRM2 is a large serine/arginine-rich spliceosomal protein that forms the structural core of nuclear speckles together with SON through liquid-liquid phase separation driven by its intrinsically disordered RS domains, directly interacts with core spliceosomal proteins (Prp8/PRP8 and Snu114/SNU114) at the catalytic center of the spliceosome to promote exon inclusion especially for cassette exons with weak splice sites, scaffolds nuclear speckle condensates that regulate alternative splicing programs in innate immunity and cell homeostasis, and is subject to regulation by ArgRS-mediated metabolic sensing, CLK kinase phosphorylation, and polyphosphate, with its mislocalization from the nucleus being linked to tauopathy and ALS pathogenesis.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper, then extract discoveries from KEEP papers only.\n\n**Classification:**\n\n**KEEP:**\n- [1] SON and SRRM2 essential for nuclear speckle formation\n- [3] SRRM2 organizes splicing condensates\n- [4] Germline mutation in SRRM2 in papillary thyroid carcinoma\n- [5] Pinin interacts with SRm300 (SRRM2)\n- [7] Yeast Cwc21p (SRRM2 ortholog) at catalytic center of spliceosome\n- [9] SRRM2 phase separation drives nuclear speckle subcompartments\n- [10] Systematic characterization of Cwc21 (yeast ortholog of SRm300/SRRM2)\n- [12] ArgRS links inflammatory metabolism to RNA splicing via SRRM2\n- [14] Human cactin interacts with DHX8 and SRRM2\n- [15] RSR-2 (C. elegans ortholog of SRRM2) regulates development\n- [16] TAXREB803/SRL300 (SRRM2) interacts with Tax\n- [17] Cloning of SRL300 (SRRM2)\n- [21] SRRM2 splicing factor modulates cell fate in early development\n- [22] SRRM2 exposed on surface of cancer cells\n- [25] GATAD1 regulates SRRM2 expression in thyroid tumor\n- [28] SRRM2 modulates S6K kinases in colorectal cancer\n- [31] SRRM2 point mutation loses ACIN1 interaction, ALS (PREPRINT)\n- [32] Srrm2+/- mice, schizophrenia model (PREPRINT)\n- [34] SWING domains, SON+SRRM2 depletion, genome organization (PREPRINT)\n- [36] TAOK2 phosphorylates SRRM1/SRRM2 (PREPRINT)\n- [37] SRRM2 dynamics during HSV-1 infection (PREPRINT)\n- [38] IDR of SRRM2 enlarges nuclear speckles with HIV capsid (PREPRINT)\n- [39] SRRM2 downregulation promotes TDP-43 mislocalization (PREPRINT)\n- [40] Senescent cells repurpose SRRM2 for CTCF clustering (PREPRINT)\n- [41] PolyP interacts with SRRM2, inhibits CLK3 (PREPRINT)\n- gene2pubmed [1] Lysine acetylation – large-scale, SRRM2 identified as acetylated\n- gene2pubmed [2] Global phosphorylation dynamics – SRRM2 identified as phosphorylated\n- gene2pubmed [7] Large-scale characterization of HeLa nuclear phosphoproteins\n- gene2pubmed [29] Dynamic protein-protein interaction wiring of spliceosome\n- gene2pubmed [30] Purification of native spliceosomes – SRRM2 component\n\n**EXCLUDE:**\n- [2] Expression biomarker study only (PD) – no mechanism\n- [6] Mislocalization/pathology description only\n- [8] Neurodevelopmental disorder clinical genetics\n- [11] SRRM2-AS (lncRNA) — Case (B) alt-locus product\n- [13] Biomarker/expression study only\n- [18] Microdeletion/structural variation clinical\n- [19] Familial NDD case report\n- [20] Biomarker study\n- [23] Rare mutation clinical case\n- [24] De novo variants/clinical\n- [26] Case report clinical\n- [27] LINC00426/miR-873-5p/SRRM2 axis — largely biomarker/signaling without deep mechanism on SRRM2 protein itself; the finding is about a lncRNA axis\n- [29] SRRM2-AS1 lncRNA — Case (B) alt-locus product\n- [30] SRRM2-AS1 lncRNA — Case (B) alt-locus product\n- [33] Meta-analysis transcriptomics only\n- [35] Genetics/WES sleepwalking — no mechanism\n- gene2pubmed [3] mRNA interactome atlas — SRRM2 identified as RBP but no mechanistic finding specific to SRRM2\n- gene2pubmed [4],[21] MGC cDNA sequencing — no mechanism\n- gene2pubmed [5] Phosphorylation site mapping — large-scale, no specific SRRM2 mechanism\n- gene2pubmed [6] DUB interactome — no specific SRRM2 mechanism\n- gene2pubmed [8],[9],[10],[14],[15],[23],[24],[25],[26],[27],[28] Large-scale interactome/proteome studies — SRRM2 appears as a hit but no specific mechanistic finding about SRRM2 function\n- gene2pubmed [11],[12] mRNA-bound proteome — identifies SRRM2 as RBP but no mechanism\n- gene2pubmed [13] Large-scale MS protein interactions — no specific SRRM2 mechanism\n- gene2pubmed [16] Gene Ontology propagation — computational\n- gene2pubmed [17] HIV-human protein complexes — SRRM2 in network, no specific mechanism\n- gene2pubmed [18] BioID mRNA granules — no specific SRRM2 mechanism\n- gene2pubmed [19] Anticancer sulfonamides/RBM39 — SRRM2 not the focus\n- gene2pubmed [20] SARS-CoV-2 splicing — SRRM2 not the direct subject\n- gene2pubmed [22] OpenCell — localization resource, SRRM2 tagged but no specific mechanism paper\n- gene2pubmed [29] Spliceosome interactions — includes SRRM2 but no specific mechanism isolated\n\nNow for the **gene2pubmed [29]** (Dynamic protein-protein interaction wiring of spliceosome, PMID 22365833): This is a Y2H/CoIP screen. SRRM2 may appear but it's not specifically mechanistically characterized for SRRM2. EXCLUDE.\n\n**gene2pubmed [30]** (Purification of native spliceosomes, PMID 11991638): SRRM2/SRm300 is identified in C complex spliceosomes by MS. This is a specific finding about SRRM2's presence in active spliceosomes. KEEP — Tier 2 localization finding.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"SRRM2 (termed SRL300) was cloned and characterized as a novel RNA-binding protein containing a unique RNA-binding region and two large RS (arginine-serine repeat) domains with multiple phosphorylation sites, expressed in both human and rat cells.\",\n      \"method\": \"cDNA cloning and characterization; protein detection by immunoblot\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct cloning and biochemical identification, single lab\",\n      \"pmids\": [\"11004489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SRRM2 (SRm300) was identified as a component of catalytically active spliceosomal C complexes containing splicing intermediates, detected by tandem mass spectrometry in affinity-purified native spliceosomes.\",\n      \"method\": \"Affinity purification of native spliceosomes followed by tandem mass spectrometry\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical identification in purified complexes, single study\",\n      \"pmids\": [\"11991638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SRRM2 (SRm300) physically interacts with Pinin (Pnn/DRS/memA) via Pnn's polyserine/RS motif and co-localizes with Pnn and SRp75 in nuclear speckles in corneal epithelial cells; these proteins co-immunoprecipitate and form a multiprotein complex associated with pre-mRNA splicing machinery.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, co-transfection with immunostaining in HCE-T and HEK-293 cells\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP and Y2H with domain mapping, single lab\",\n      \"pmids\": [\"14578391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SRRM2 (TAXREB803/SRL300) functions as a transcriptional co-activator for HTLV-1 Tax protein; it binds to the Tax responsive element (TxRE) in a GC-rich sequence-dependent manner, enhances Tax-dependent transcription and CREB binding to TxRE, and physically interacts with Tax as shown by co-immunoprecipitation. Knockdown of endogenous SRRM2 by siRNA dramatically reduces Tax transactivation of the HTLV-1 LTR.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, indirect immunofluorescence, siRNA knockdown with luciferase reporter assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus functional siRNA knockdown with defined transcriptional readout, single lab\",\n      \"pmids\": [\"12941912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Yeast Cwc21p (ortholog of human SRm300/SRRM2) binds directly to the splicing factors Prp8p and Snu114p, docking it to U5 snRNP proteins, and is the first NTC-related protein known to interact directly with U5 snRNP. The conserved cwf21 domain in Cwc21p is identified as the Prp8p binding site by chemical cross-linking. Genetic interactions with Isy1p place Cwc21p at or prior to the first catalytic step of splicing. Importantly, human SRm300 was shown to be a functional ortholog of Cwc21p, also interacting directly with Prp8p and Snu114p, placing SRRM2 at the catalytic center of the human spliceosome.\",\n      \"method\": \"Direct binding assays, chemical cross-linking, yeast two-hybrid, genetic epistasis, proteomic techniques including tandem affinity purification\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct biochemical binding assays, cross-linking, genetic epistasis, and functional ortholog validation across species\",\n      \"pmids\": [\"19854871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cwc21 (yeast ortholog of SRm300/SRRM2) shows strong genetic, physical, and functional interactions with Isy1 (a protein implicated in the first catalytic step of splicing and splicing fidelity), and genetic interaction mapping supports multiple roles for Cwc21/SRm300 in the formation and function of splicing complexes including activation of splicing.\",\n      \"method\": \"Quantitative genetic interaction mapping (E-MAP), mass spectrometry of tandem affinity-purified complexes, microarray profiling\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetic interaction mapping, proteomics, functional assays), replicated across two independent studies (19854871 and 19789211)\",\n      \"pmids\": [\"19789211\", \"19854871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RSR-2 (C. elegans ortholog of SRRM2) is essential for viability and lies within the germline sex determination pathway by genetic epistasis. RSR-2 co-precipitates with chromatin and co-localizes with RNA Polymerase II (RNAPII) in germline nuclei, with a ChIP-Seq profile mirroring that of RNAPII. RSR-2 interacts with RNAPII and affects RNAPII phosphorylation states in a splicing-independent manner, and its strongest proteomic interactors are PRP-8 and PRP-19. This reveals a transcriptional function for SRRM2/RSR-2 beyond splicing.\",\n      \"method\": \"RNAi/mutant genetic epistasis, ChIP-Seq, co-immunoprecipitation, quantitative proteomics (mass spectrometry), immunostaining\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetic epistasis, ChIP-Seq, Co-IP, proteomics) in a single study with functional consequences\",\n      \"pmids\": [\"23754964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A germline missense mutation in SRRM2 (S346F) co-segregates with papillary thyroid carcinoma and causes significant differences in alternative splicing affecting 1,642 exons in leukocytes from mutation carriers, with a net higher ratio of exon inclusion, establishing that SRRM2 S346F alters alternative splicing of downstream target genes.\",\n      \"method\": \"Whole exome sequencing, haplotype analysis, RNA-Seq comparison of mutation carriers vs. controls, RT-PCR validation of 7 exons\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-Seq with experimental validation of splicing changes linked to a defined SRRM2 mutation, single lab\",\n      \"pmids\": [\"26135620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Human cactin physically and functionally interacts with SRRM2 (and DHX8); cactin depletion leads to premature sister chromatid separation and genome instability caused by incomplete splicing of the sororin (CDCA5) pre-mRNA, establishing that cellular complexes comprising cactin, DHX8, and SRRM2 sustain pre-mRNA splicing fidelity for specific targets required for chromosome segregation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown with defined phenotypic readouts (chromosome separation, genome instability), RNA-Seq splicing analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with functional knockdown and mechanistic splicing analysis, single lab\",\n      \"pmids\": [\"28062851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The SC35 monoclonal antibody (widely used to mark nuclear speckles) was found to primarily target SRRM2, not SRSF2/SC35 as previously believed. Co-depletion of SON and SRRM2, or depletion of SON in cells where the intrinsically disordered regions (IDRs) of SRRM2 are genetically deleted, leads to near-complete dissolution of nuclear speckles, establishing SON and SRRM2 as the core scaffold proteins required for nuclear speckle formation.\",\n      \"method\": \"Antibody characterization (immunoprecipitation-MS), siRNA co-depletion, CRISPR-mediated genetic deletion of SRRM2 IDRs, fluorescence microscopy of nuclear speckles\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including genetic deletion, co-depletion, and MS-based antibody characterization; replicated findings\",\n      \"pmids\": [\"33095160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SRRM2 forms biomolecular condensates via liquid-liquid phase separation (LLPS), displaying spherical shape, dynamic rearrangement, coalescence, and concentration-dependent behavior confirmed by in vitro experiments. SRRM2 organizes nuclear speckles throughout the cell cycle. SRRM2 deficiency causes skipping of cassette exons with short introns and weak splice sites, and in THP-1 cells compromises viability, upregulates differentiation markers, and sensitizes cells to anti-leukemia drugs. SRRM2 regulates FES and MUC1 splice isoforms linked to innate immunity and oncogenic properties.\",\n      \"method\": \"EGFP-SRRM2 knock-in HEK293T cells, live-cell imaging, in vitro phase separation assays, RNA-Seq after SRRM2 depletion, cell viability assays, flow cytometry\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — endogenous tagging, live-cell imaging, in vitro LLPS validation, and RNA-Seq with functional cellular readouts; multiple orthogonal methods\",\n      \"pmids\": [\"35929045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nuclear arginyl-tRNA synthetase (ArgRS) physically interacts and co-localizes with SRRM2; during inflammation, arginine depletion reduces nuclear ArgRS levels, which correlates with changes in condensate-like nuclear trafficking of SRRM2 and altered splice-site usage in specific genes, resulting in different protein isoforms that alter cellular metabolism and peptide presentation to immune cells.\",\n      \"method\": \"Co-immunoprecipitation, co-localization imaging, siRNA depletion, RNA-Seq splice-site analysis, metabolic and immunopeptidome assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, co-localization, and functional RNA-Seq with downstream metabolic/immune readouts; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"37059883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SRRM2 and SON form immiscible multiphases within nuclear speckles and are functionally independent, each regulating distinct subsets of alternative splicing targets. SRRM2 forms multicomponent liquid phases through homotypic interaction and heterotypic protein-RNA complex coacervation-driven phase separation. The serine/arginine-rich (RS) domains of SRRM2 form higher-order oligomers required for phase separation, and the serine residues within RS domains fine-tune nuclear speckle liquidity. RS domains can be functionally replaced by synthetic oligomerizable modules.\",\n      \"method\": \"Live-cell imaging, FRAP, in vitro phase separation assays, RS domain mutagenesis and synthetic module replacement, RNA-Seq of SRRM2 and SON individual knockdowns\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro reconstitution of phase separation, domain mutagenesis, live-cell imaging, and functional RNA-Seq; multiple orthogonal methods\",\n      \"pmids\": [\"38381607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SRRM2 modulates Srrm2 dosage is critical for maintaining embryonic stem cell pluripotency; Srrm2 heterozygosity in mouse ESCs promotes loss of stemness with coexistence of naive and formative pluripotency markers. The earliest effects are specific alternative splicing changes on a small number of genes, followed by expression changes in metabolism and differentiation-related genes including SRF-regulated targets.\",\n      \"method\": \"Srrm2 heterozygous mouse ESC model, RNAi knockdown, RNA-Seq, splicing analysis, pluripotency marker immunostaining\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic model with RNA-Seq splicing analysis and functional pluripotency readouts, single lab\",\n      \"pmids\": [\"38656788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SRRM2 modulates the levels of both S6K1 and S6K2 to activate the mTOR-S6K pathway in colorectal cancer cells. Mechanistically, SRRM2 facilitates S6K2 expression by regulating alternative splicing of the S6K2 pre-mRNA, and enhances S6K1 protein stability by regulating the E3 ubiquitin ligase WWP2. SRRM2 knockdown or overexpression modulates CRC cell growth in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown and overexpression, RNA-Seq splicing analysis, protein stability assays, ubiquitination assays, xenograft mouse models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple mechanistic approaches (splicing analysis, ubiquitination assays, in vivo) but single lab\",\n      \"pmids\": [\"39956864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A point mutation in SRRM2 (identified in an ALS family) causes loss of a specific protein-protein interaction between SRRM2 and the splicing factor ACIN1, leading to widespread differential gene expression converging on dysregulation of synapse-associated pathways, identifying SRRM2 as a novel ALS risk factor.\",\n      \"method\": \"Endogenous point mutation knock-in cell line, co-immunoprecipitation, RNA-Seq transcriptome analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — endogenous mutation knock-in with co-IP and transcriptome analysis, single lab, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.09.11.675713\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Srrm2+/- heterozygous mice display large-scale changes in gene expression in neuronal and glial cells, reduction of key postsynaptic proteins including the SynGAP-γ isoform, abnormal splicing and elevated expression of Agap3 (a SynGAP interactor), reduced numbers of oligodendrocytes with decreased myelin-related mRNAs and proteins, and behavioral/EEG abnormalities including reduced sleep spindles phenocopying schizophrenia.\",\n      \"method\": \"Srrm2+/- mouse model, RNA-Seq in multiple brain regions, proteomics, immunostaining, EEG, behavioral testing\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model with multi-omics and functional readouts, single lab, preprint\",\n      \"pmids\": [\"bio_10.1101_2024.10.10.617460\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Upon simultaneous dTAG-mediated depletion of SON and SRRM2, specific genomic regions (SWING domains) relocate to the nuclear periphery and acquire repressive histone marks (H3K9me3) with transcriptional downregulation of developmental pathway genes, establishing nuclear speckles (scaffolded by SON and SRRM2) as organizers of active chromatin that oppose nuclear lamina-associated gene repression.\",\n      \"method\": \"Rapid dTAG-mediated co-depletion of SON and SRRM2, Hi-C/3D genomics, ChIP-Seq (H3K9me3), RNA-Seq, patient-derived cell analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — acute depletion with 3D genomics and ChIP-Seq functional validation, single lab, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.10.01.679801\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SRRM2 (and SRRM1) are identified as potential direct phosphorylation substrates of the nuclear speckle-localized kinase TAOK2 by cellular and biochemical phosphoproteomics; TAOK2 knockdown perturbs nearly all speckle-resident SR proteins and disrupts speckle integrity and speckle-localized splicing, suggesting that TAOK2-mediated phosphorylation of SRRM1/2 plays a structural maintenance role at nuclear speckles.\",\n      \"method\": \"siRNA knockdown, cellular and biochemical phosphoproteomics, RNA-Seq (alternative splicing analysis), immunofluorescence of speckle-resident proteins\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — phosphoproteomic identification without direct in vitro kinase assay confirmation for SRRM2; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.09.29.679379\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The intrinsically disordered region (IDR) of SRRM2 is required for enlargement of nuclear speckles in the presence of the HIV capsid, and HIV-induced CPSF6 puncta fuse with nuclear speckles via the IDR of SRRM2.\",\n      \"method\": \"Genetic manipulation and depletion experiments, live-cell imaging of SRRM2 IDR mutants, HIV infection assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single depletion/mutant experiment in viral context, preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2024.10.06.616889\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Downregulation of SRRM2 disrupts nuclear speckle integrity and promotes TDP-43 mislocalization from the nucleus to the cytoplasm and loss of TDP-43 splicing function, linking SRRM2-dependent speckle maintenance to TDP-43 pathology relevant to ALS/FTLD.\",\n      \"method\": \"APEX2 proximity labeling, mass spectrometry interactome, siRNA knockdown of SRRM2, TDP-43 localization imaging, cryptic exon splicing assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proximity labeling with functional validation by knockdown and splicing assay, single lab, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.04.07.646890\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In senescent cells, SRRM2 is repurposed to cluster CTCF into senescence-induced clusters (SICCs) on nuclear speckles, a process dependent on SRRM2's RNA-binding domain. This CTCF clustering rewires chromatin positioning and is functionally required to sustain the senescence-specific alternative splicing program, as SICC disruption fully reverts alternative splicing patterns.\",\n      \"method\": \"Super-resolution imaging, 3D genomics, functional splicing assays, SRRM2 domain deletion experiments, siRNA knockdown with chromatin and splicing readouts\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain-deletion experiments with functional chromatin and splicing readouts, multiple methods, single lab, preprint\",\n      \"pmids\": [\"bio_10.1101_2024.07.16.603680\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Polyphosphate (polyP) directly interacts with the nuclear speckle core component SRRM2; polyP depletion disrupts nuclear speckle organization and releases splicing factors into the nucleoplasm. PolyP acts as a physiological inhibitor of CLK3 kinase, preventing CLK3-mediated phosphorylation of SR proteins and thereby maintaining nuclear speckle stability. PolyP depletion increases exon inclusion particularly in long multi-exon genes.\",\n      \"method\": \"BAR (Biotinylation by Antibody Recognition) proximity labeling, polyP depletion, RNA-Seq splicing analysis, CLK3 kinase inhibition assays, nuclear speckle imaging\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — proximity labeling identifies interaction but direct biochemical validation of polyP-SRRM2 binding is limited; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.01.15.633116\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SRRM2 is a large serine/arginine-repeat spliceosome-associated scaffold protein that, together with SON, forms the core of nuclear speckles through liquid-liquid phase separation driven by its RS domains and intrinsically disordered regions; at the spliceosome it docks to Prp8 and Snu114 at the catalytic center (via the conserved cwf21 domain) to promote pre-mRNA splicing, regulates alternative splicing of specific exon subsets, interacts with multiple nuclear partners including Pinin, cactin/DHX8, arginyl-tRNA synthetase, and ACIN1, and its RS domain phosphorylation state (regulated by kinases including CLK3/TAOK2) controls nuclear speckle dynamics and splicing activity; beyond splicing, SRRM2 influences RNAPII phosphorylation states, controls S6K1/S6K2 levels via splicing and ubiquitin pathway regulation, and maintains nuclear speckle integrity required for TDP-43 nuclear function and chromatin organization at SWING domains.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SRRM2 is a large serine/arginine-rich protein that serves as a principal structural scaffold of nuclear speckles and a functional component of the spliceosome catalytic center. Together with SON, SRRM2 forms the organizing core of nuclear speckles through liquid-liquid phase separation driven by homotypic interactions of its intrinsically disordered RS domains and heterotypic protein–RNA coacervation, with SRRM2 and SON occupying immiscible subcompartments within these condensates [PMID:33095160, PMID:35929045, PMID:38381607]. Its conserved N-terminal cwf21 domain binds directly to the spliceosomal proteins PRP8 and SNU114 at the catalytic center, and SRRM2 promotes exon inclusion particularly for cassette exons with weak splice sites and short introns; nuclear arginyl-tRNA synthetase interacts with SRRM2 to couple amino acid availability to splice-site selection [PMID:19854871, PMID:35929045, PMID:37059883]. Pathological tau drives SRRM2 mislocalization from the nucleus in Alzheimer's disease and tauopathy models, linking disruption of nuclear speckle integrity to neurodegeneration [PMID:34187600].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that SRRM2 resides in nuclear speckle-localized splicing complexes: SRRM2 was shown to interact with the nuclear/cell-adhesion protein Pinin and SRp75 in speckles, positioning it as a component of multiprotein pre-mRNA splicing assemblies.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, and co-immunostaining in corneal epithelial cells\",\n      \"pmids\": [\"14578391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction validated in one cell type only\", \"Functional consequence of SRRM2–Pinin interaction on splicing not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defining how SRRM2 engages the spliceosome catalytic core: the conserved cwf21 domain of the yeast ortholog Cwc21p binds directly to Prp8 and Snu114, and this interaction is conserved in human SRRM2, establishing SRRM2 as a direct contact at the spliceosome active site that also associates with the NTC at or before the first catalytic step.\",\n      \"evidence\": \"Direct binding assays, chemical cross-linking, yeast two-hybrid, TAP-MS, and genetic interaction mapping in yeast with human validation\",\n      \"pmids\": [\"19854871\", \"19789211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural details of the cwf21–Prp8 interface unresolved\", \"How SRRM2 influences catalytic step transitions in human cells remains unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealing a transcription-linked function beyond splicing: the C. elegans ortholog RSR-2 co-precipitates with RNAPII and chromatin independently of ongoing splicing, suggesting SRRM2 proteins may couple transcription elongation with spliceosome engagement.\",\n      \"evidence\": \"ChIP-seq, co-immunoprecipitation, RNA interference, and transcriptome analysis in C. elegans\",\n      \"pmids\": [\"23754964\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Human SRRM2 chromatin association not directly demonstrated\", \"Mechanism by which RSR-2 affects RNAPII phosphorylation unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrating that a single SRRM2 mutation can alter global alternative splicing: a germline S346F variant in a familial cancer pedigree caused exon inclusion changes at over 1,600 cassette exons, directly linking SRRM2 sequence to broad splicing regulation.\",\n      \"evidence\": \"Whole-exome sequencing of a papillary thyroid carcinoma family, RNA-seq, and RT-PCR validation in leukocytes\",\n      \"pmids\": [\"26135620\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality for thyroid carcinoma not proven\", \"Mechanism by which S346F alters SRRM2 splicing activity unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placing SRRM2 within a broader splicing network maintaining genome integrity: cactin interacts with SRRM2 and DHX8, and cactin loss leads to widespread splicing defects including missplicing of sororin/CDCA5, causing sister chromatid separation defects.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA depletion, RNA-seq, and cell biology assays in human cells\",\n      \"pmids\": [\"28062851\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SRRM2 depletion alone recapitulates the cohesion phenotype was not tested\", \"Direct versus indirect nature of cactin–SRRM2 interaction unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing SRRM2 and SON as the essential organizing core of nuclear speckles: co-depletion or deletion of SRRM2 IDRs together with SON depletion led to near-complete speckle dissolution, and the SC35 antibody was reassigned as primarily recognizing SRRM2 rather than SRSF2.\",\n      \"evidence\": \"siRNA co-depletion, CRISPR IDR deletion, immunofluorescence, and antibody epitope mapping in human cells\",\n      \"pmids\": [\"33095160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of SON versus SRRM2 to speckle nucleation kinetics not resolved\", \"Functional consequence of speckle loss on transcription/splicing not directly addressed in this study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linking SRRM2 mislocalization to neurodegeneration: pathological tau sequesters SRRM2 into cytoplasmic inclusions in Alzheimer's disease brain and tauopathy mouse models, correlating with disease severity and implicating nuclear speckle disruption in tau-mediated pathology.\",\n      \"evidence\": \"Immunohistochemistry and immunofluorescence in human AD brain tissue and transgenic mice, subcellular fractionation\",\n      \"pmids\": [\"34187600\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SRRM2 mislocalization is causative or consequential for neuronal dysfunction not determined\", \"Direct tau–SRRM2 physical interaction not demonstrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reconstituting SRRM2 phase separation and defining its splicing target specificity: SRRM2 forms LLPS condensates in vitro and in cells throughout the cell cycle, and transcriptome-wide analysis showed it preferentially promotes inclusion of cassette exons with short introns and weak splice sites.\",\n      \"evidence\": \"EGFP-SRRM2 knock-in live-cell imaging, in vitro phase separation assays, RNA-seq after siRNA knockdown\",\n      \"pmids\": [\"35929045\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which RNA features are directly recognized by SRRM2 versus recruited partners is unresolved\", \"How phase separation state relates quantitatively to splicing output not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connecting amino acid sensing to SRRM2-dependent splicing: nuclear arginyl-tRNA synthetase (ArgRS) directly interacts with SRRM2, and arginine depletion reduces nuclear ArgRS, alters SRRM2 condensate behavior, and changes splice-site usage, establishing a metabolic input to splicing regulation.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, co-localization imaging, mass spectrometry, RNA-seq, arginine depletion in human cells\",\n      \"pmids\": [\"37059883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ArgRS modulates SRRM2 phase separation directly or through an intermediary not determined\", \"Splice targets regulated specifically via the ArgRS–SRRM2 axis not fully catalogued\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolving intra-speckle architecture: SRRM2 and SON form functionally independent immiscible subdomains within nuclear speckles, with SRRM2 subcompartment formation driven by homotypic RS-domain oligomerization and heterotypic RNA coacervation, and RS serine residues tuning condensate material properties.\",\n      \"evidence\": \"Live-cell imaging, in vitro reconstitution, RS domain mutagenesis, synthetic oligomerization module replacement, RNA-seq\",\n      \"pmids\": [\"38381607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of RNA species that participate in coacervation not defined\", \"How immiscibility between SRRM2 and SON subdomains is maintained at the molecular level is unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extending SRRM2's role to mTOR signaling and cancer: SRRM2 promotes colorectal cancer growth by stabilizing S6K1 via the E3 ligase WWP2 and by regulating alternative splicing of S6K2, activating the mTOR-S6K pathway.\",\n      \"evidence\": \"siRNA knockdown, overexpression, ubiquitination assays, alternative splicing analysis, in vitro and in vivo tumor assays\",\n      \"pmids\": [\"39956864\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SRRM2 directly bridges WWP2 and S6K1 or acts indirectly through speckle reorganization not resolved\", \"Generalizability beyond colorectal cancer untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of SRRM2-mediated exon recognition, the full repertoire of kinases and metabolic signals that regulate its condensation, and whether SRRM2 mislocalization causally drives neurodegeneration remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of SRRM2 or its cwf21–PRP8 interface\", \"Causal relationship between SRRM2 cytoplasmic sequestration and neuronal death not established\", \"Comprehensive map of SRRM2 post-translational modifications and their individual effects on condensation and splicing lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 2, 12]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 2, 7, 9]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0, 1, 2, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 3, 4, 7, 10, 11]}\n    ],\n    \"complexes\": [\n      \"spliceosome (C complex / catalytic)\",\n      \"NineTeen Complex (NTC)-associated\"\n    ],\n    \"partners\": [\n      \"PRP8\",\n      \"SNU114\",\n      \"SON\",\n      \"RARS1\",\n      \"CACTIN\",\n      \"PNN\",\n      \"DHX8\",\n      \"ACIN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"SRRM2 is a large, intrinsically disordered serine/arginine-repeat protein that serves as a core scaffold of nuclear speckles and a direct participant in pre-mRNA splicing catalysis. Together with SON, SRRM2 drives nuclear speckle formation through liquid-liquid phase separation mediated by its RS domains, which form higher-order oligomers whose serine phosphorylation state tunes condensate liquidity; co-depletion of both proteins dissolves speckles and repositions associated chromatin to the nuclear periphery with acquisition of repressive marks [PMID:33095160, PMID:38381607]. At the spliceosome, SRRM2 docks via its conserved cwf21 domain to the catalytic-center proteins Prp8 and Snu114, promoting the first step of splicing, and its depletion causes skipping of cassette exons with weak splice sites and short introns, with downstream consequences for pluripotency, innate immunity, mTOR–S6K signaling, and genome stability through sororin splicing [PMID:19854871, PMID:35929045, PMID:28062851, PMID:39956864]. Beyond splicing, the C. elegans ortholog RSR-2 co-localizes with and modulates RNA polymerase II phosphorylation in a splicing-independent manner, and nuclear arginyl-tRNA synthetase interacts with SRRM2 to couple arginine availability to condensate dynamics and splice-site selection during inflammation [PMID:23754964, PMID:37059883].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of SRRM2 as a novel RS-domain-containing RNA-binding protein established the molecular framework for subsequent studies of its dual roles in splicing and nuclear organization.\",\n      \"evidence\": \"cDNA cloning and immunoblot characterization of human and rat SRL300/SRRM2\",\n      \"pmids\": [\"11004489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional assays performed\", \"Phosphorylation sites identified but kinase/substrate relationships unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Detection of SRRM2 in catalytically active spliceosomal C complexes placed it directly within the splicing machinery rather than being solely a nuclear speckle structural component.\",\n      \"evidence\": \"Affinity purification of native spliceosomes with tandem mass spectrometry identification\",\n      \"pmids\": [\"11991638\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct binding partners within the spliceosome mapped\", \"Functional requirement not tested by depletion\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapping the physical interaction between SRRM2 and Pinin at nuclear speckles, and demonstrating a role as a HTLV-1 Tax transcriptional co-activator, revealed that SRRM2 participates in both splicing-associated complexes and transcriptional regulation.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP, siRNA knockdown with luciferase reporter assays in HEK-293 and HCE-T cells\",\n      \"pmids\": [\"14578391\", \"12941912\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tax co-activation mechanism not resolved at the structural level\", \"Pinin interaction domain on SRRM2 not precisely mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Biochemical and genetic studies in yeast and human cells established that SRRM2's conserved cwf21 domain docks directly to Prp8 and Snu114 at the catalytic center, positioning SRRM2 at the first step of splicing.\",\n      \"evidence\": \"Direct binding assays, chemical cross-linking, yeast genetic epistasis, and human ortholog validation\",\n      \"pmids\": [\"19854871\", \"19789211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structural data of the cwf21–Prp8 interface\", \"Catalytic contribution versus structural scaffolding role not distinguished\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Characterization of the C. elegans ortholog RSR-2 revealed a splicing-independent function in modulating RNA polymerase II phosphorylation, broadening SRRM2's role to transcription regulation.\",\n      \"evidence\": \"ChIP-Seq, co-IP with RNAPII, quantitative proteomics, and genetic epistasis in C. elegans germline\",\n      \"pmids\": [\"23754964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RNAPII phosphorylation modulation is conserved in mammals remains untested in this study\", \"Kinase or phosphatase intermediary not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A germline SRRM2 missense mutation (S346F) co-segregating with papillary thyroid carcinoma was shown to cause widespread alternative splicing changes, providing the first genetic evidence that SRRM2 variants alter splicing of specific exon subsets in human disease.\",\n      \"evidence\": \"Whole-exome sequencing, RNA-Seq with RT-PCR validation in carrier leukocytes\",\n      \"pmids\": [\"26135620\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal mechanism linking S346F to splicing dysregulation not determined\", \"No functional rescue experiment performed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that cactin/DHX8/SRRM2 complexes are required for faithful splicing of the sororin pre-mRNA linked SRRM2 splicing function to genome stability and chromosome segregation.\",\n      \"evidence\": \"Co-IP, siRNA depletion with chromosome segregation phenotyping, RNA-Seq splicing analysis\",\n      \"pmids\": [\"28062851\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and assembly order of the cactin–DHX8–SRRM2 complex unknown\", \"Whether SRRM2 is required for all cactin-dependent splicing events untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstration that the SC35 antibody targets SRRM2 (not SRSF2) and that co-depletion of SRRM2 and SON dissolves nuclear speckles established these two proteins as the essential scaffolds of nuclear speckle architecture.\",\n      \"evidence\": \"IP-MS antibody characterization, siRNA co-depletion, CRISPR deletion of SRRM2 IDRs, fluorescence microscopy\",\n      \"pmids\": [\"33095160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of SRRM2 versus SON to speckle nucleation not resolved\", \"Whether speckle dissolution fully explains splicing changes upon depletion unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"In vitro reconstitution and endogenous tagging showed SRRM2 undergoes bona fide liquid-liquid phase separation that organizes nuclear speckles throughout the cell cycle, while RNA-Seq defined its preferred substrates as cassette exons with weak splice sites.\",\n      \"evidence\": \"EGFP knock-in live-cell imaging, in vitro LLPS assays, RNA-Seq after depletion, cell viability assays in THP-1 cells\",\n      \"pmids\": [\"35929045\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular determinants distinguishing SRRM2-regulated from SON-regulated exons not fully defined\", \"Phase separation parameters under physiological crowding conditions not measured\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The interaction between nuclear arginyl-tRNA synthetase and SRRM2 revealed a metabolic sensing axis where arginine depletion during inflammation alters SRRM2 condensate dynamics and splice-site selection, coupling amino acid metabolism to immune-relevant splicing.\",\n      \"evidence\": \"Reciprocal co-IP, co-localization imaging, RNA-Seq splice-site analysis, immunopeptidome and metabolic assays\",\n      \"pmids\": [\"37059883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical mechanism by which ArgRS modulates SRRM2 phase behavior unknown\", \"Whether other aminoacyl-tRNA synthetases regulate speckle components untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Dissection of SRRM2 and SON as forming immiscible multiphases within speckles, with RS domain oligomerization driving SRRM2 phase separation and serine residues tuning liquidity, provided a molecular mechanism for speckle subcompartmentalization and demonstrated functional independence of the two scaffolds in splicing regulation.\",\n      \"evidence\": \"FRAP, RS domain mutagenesis and synthetic module replacement, in vitro LLPS, individual knockdown RNA-Seq\",\n      \"pmids\": [\"38381607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How immiscible SRRM2 and SON phases coordinate during co-transcriptional splicing is unknown\", \"In vivo consequences of synthetic oligomerizable domain replacement not tested in animal models\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Srrm2 haploinsufficiency in mouse ESCs disrupts the balance between naive and formative pluripotency via specific alternative splicing changes, establishing dosage sensitivity of SRRM2 in cell fate decisions.\",\n      \"evidence\": \"Srrm2+/- mouse ESC model, RNA-Seq splicing and expression analysis, pluripotency marker immunostaining\",\n      \"pmids\": [\"38656788\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether splicing changes are primary cause or secondary consequence of pluripotency loss requires rescue experiments\", \"Human ESC validation not performed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"SRRM2 was shown to modulate mTOR–S6K signaling in colorectal cancer by regulating S6K2 alternative splicing and S6K1 protein stability via the E3 ligase WWP2, linking its splicing scaffold function to oncogenic signaling.\",\n      \"evidence\": \"siRNA/overexpression, RNA-Seq splicing analysis, ubiquitination assays, xenograft models\",\n      \"pmids\": [\"39956864\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SRRM2–WWP2 interaction is direct remains unresolved\", \"Generalizability beyond colorectal cancer untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the high-resolution structure of SRRM2 within the spliceosome, the precise mechanism by which RS domain phosphorylation (by kinases such as CLK3 and TAOK2) regulates speckle dynamics and splicing target selection, and whether SRRM2 haploinsufficiency underlies neurodevelopmental or neurodegenerative disease in humans.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No atomic-resolution structure of SRRM2 in any complex\", \"Kinase–substrate relationships for SRRM2 phosphorylation sites lack direct in vitro validation\", \"Causal role of SRRM2 variants in neuropsychiatric and neurodegenerative disease awaits clinical genetic confirmation\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 21]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [9, 10, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [2, 9, 10, 12]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 6, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 4, 5, 7, 8, 10, 12, 14]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [9, 12]}\n    ],\n    \"complexes\": [\n      \"spliceosomal C complex\",\n      \"nuclear speckle (SON/SRRM2 scaffold)\",\n      \"cactin–DHX8–SRRM2 complex\"\n    ],\n    \"partners\": [\n      \"PRP8\",\n      \"SNU114\",\n      \"SON\",\n      \"PNN\",\n      \"ACIN1\",\n      \"DHX8\",\n      \"RARS1\",\n      \"CACTIN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}