{"gene":"SRRM2","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":2020,"finding":"SON and SRRM2 form the core scaffold of nuclear speckles: depletion of SON alone causes partial disassembly, but co-depletion of SON and SRRM2, or depletion of SON in cells where SRRM2's intrinsically disordered regions (IDRs) are genetically deleted, causes near-complete dissolution of nuclear speckles. The SC35 monoclonal antibody, widely used as a nuclear speckle marker, was found to principally recognize SRRM2, not SRSF2.","method":"siRNA co-depletion, CRISPR-mediated IDR deletion, immunofluorescence, immunoblot, proteomics","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic depletion with multiple orthogonal methods (siRNA, CRISPR deletion, imaging), rigorous controls, replicated across cell lines","pmids":["33095160"],"is_preprint":false},{"year":2022,"finding":"SRRM2 forms biomolecular condensates consistent with liquid-liquid phase separation (spherical shape, dynamic rearrangement, coalescence, concentration dependence confirmed in vitro). SRRM2 organizes nuclear speckles throughout the cell cycle. SRRM2 deficiency causes skipping of cassette exons with short introns and weak splice sites. In THP-1 myeloid-like cells, SRRM2 depletion compromises cell viability, upregulates differentiation markers, and sensitizes cells to anti-leukemia drugs. SRRM2 induces a FES splice isoform that attenuates innate inflammatory responses and MUC1 isoforms with oncogenic shedding properties.","method":"EGFP-SRRM2 knock-in HEK293T cells, live-cell imaging, in vitro phase separation assay, RNA-seq after SRRM2 depletion, cell viability assays, drug sensitivity assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (live imaging, in vitro reconstitution, transcriptomics, functional cellular assays) in a single focused study","pmids":["35929045"],"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 drives nuclear speckle subcompartmentalization via homotypic interaction (through RS domain oligomerization) and heterotypic non-selective protein-RNA coacervation-driven phase separation. Serine residues within the RS domains play an irreplaceable role in fine-tuning nuclear speckle liquidity; RS domains can be functionally replaced by synthetic oligomerizable modules for structural but not liquidity roles.","method":"Super-resolution imaging, FRAP, in vitro phase separation, domain swap/mutagenesis, RNA-seq, cell-based condensate assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution combined with domain mutagenesis and live-cell imaging, single lab with multiple orthogonal approaches","pmids":["38381607"],"is_preprint":false},{"year":2009,"finding":"Yeast Cwc21p (ortholog of human SRm300/SRRM2) binds directly to two core spliceosomal proteins, Prp8p and Snu114p (U5 snRNP), making it the first NTC-related protein known to dock directly to U5 snRNP proteins. The conserved cwf21 domain in Cwc21p is the Prp8p binding site. Cwc21p and Isy1p have related functions at or prior to the first catalytic step of splicing. Human SRm300/SRRM2 is a functional ortholog of Cwc21p, also directly interacting with Prp8p and Snu114p.","method":"Direct binding assays, chemical cross-linking, proteomic analysis of the SCwid domain, genetic interaction (suppressor/synthetic lethality), co-immunoprecipitation","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding assays with cross-linking footprinting, genetic epistasis, and demonstration of human SRm300 functional orthology in a single rigorous study","pmids":["19854871"],"is_preprint":false},{"year":2009,"finding":"Yeast Cwc21p (ortholog of SRm300/SRRM2) shows strong genetic, physical, and functional interactions with Isy1p (implicated in the first catalytic step of splicing and splicing fidelity), and associates with spliceosomal complexes, supporting a role for Cwc21/SRm300 in spliceosome activation and splicing fidelity.","method":"Quantitative genetic interaction mapping, tandem affinity purification mass spectrometry, microarray profiling","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TAP-MS and genetic interaction mapping, single lab, multiple complementary approaches","pmids":["19789211"],"is_preprint":false},{"year":2003,"finding":"SRRM2 (SRm300) physically interacts with Pinin (Pnn/DRS/memA) at the C-terminus of Pinin, and co-immunoprecipitates and co-localizes with Pinin and other SR-rich proteins (SRp75, SRrp130) in nuclear speckles in corneal epithelial cells, suggesting participation in a multiprotein nuclear complex involved in pre-mRNA processing.","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 3 / Moderate — yeast two-hybrid and co-IP, two orthogonal methods, single lab","pmids":["14578391"],"is_preprint":false},{"year":2003,"finding":"SRRM2 (as TAXREB803/SRL300) interacts with HTLV-1 Tax oncoprotein, co-immunoprecipitates with Tax, co-localizes with Tax by indirect immunofluorescence, enhances Tax-dependent transcription and CREB binding to TxRE. Knockdown of TAXREB803 by siRNA dramatically decreases Tax transactivation of the HTLV-1 LTR, identifying SRRM2 as a transcriptional coactivator for Tax.","method":"Co-immunoprecipitation, indirect immunofluorescence, luciferase reporter assay, siRNA knockdown","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP, co-localization, reporter assay, and siRNA knockdown in a single lab with multiple methods","pmids":["12941912"],"is_preprint":false},{"year":2013,"finding":"RSR-2, the C. elegans ortholog of SRm300/SRRM2, is essential for viability and acts within the germline sex determination pathway (genetic epistasis). RSR-2 colocalizes with DNA in germline nuclei and co-precipitates with chromatin, with a ChIP-Seq profile similar to RNA Polymerase II. RSR-2 recruitment to chromatin is splicing-independent. RSR-2 interacts with RNAPII and affects RNAPII phosphorylation states. Strongest interacting partners identified by proteomics are PRP-8 and PRP-19.","method":"RNAi, genetic epistasis analysis, transcriptomics, ChIP-Seq, co-immunoprecipitation with RNAPII, proteomic analysis","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-Seq, co-IP, genetic epistasis in C. elegans ortholog, single lab, multiple methods","pmids":["23754964"],"is_preprint":false},{"year":2017,"finding":"Human cactin physically and functionally interacts with SRRM2 (co-immunoprecipitation), and this complex (along with DHX8) is required for efficient pre-mRNA splicing of thousands of transcripts and for sister chromatid cohesion. Cactin depletion impairs splicing of sororin (CDCA5) pre-mRNA, causing premature sister chromatid separation.","method":"Co-immunoprecipitation, siRNA depletion, RNA-seq splicing analysis, cell biology (chromosome segregation assay)","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP plus functional depletion with defined cellular phenotype, single lab, multiple orthogonal readouts","pmids":["28062851"],"is_preprint":false},{"year":2023,"finding":"Nuclear arginyl-tRNA synthetase (ArgRS) interacts and co-localizes with SRRM2. During arginine depletion (as occurs in inflammation), nuclear ArgRS levels decrease, which correlates with changes in condensate-like nuclear trafficking of SRRM2 and altered splice-site usage in specific genes, leading to different protein isoforms that alter cellular metabolism and peptide presentation to immune cells.","method":"Co-immunoprecipitation, co-localization by imaging, arginine depletion experiments, RNA-seq splice site analysis, metabolic and immunopeptidome assays","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and co-localization with functional splice-site analysis, multiple orthogonal methods, single lab","pmids":["37059883"],"is_preprint":false},{"year":2015,"finding":"The germline missense variant S346F in SRRM2 causes a higher ratio of exon inclusion in leukocytes of carriers compared to controls (RNA-seq and experimental validation of 7 exons), consistent with altered alternative splicing activity of SRRM2 due to this mutation.","method":"RNA-seq in human leukocytes from variant carriers vs. controls, experimental validation of specific exon inclusion events by RT-PCR","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq with experimental validation of splicing changes in human carriers, single lab, multiple orthogonal validations","pmids":["26135620"],"is_preprint":false},{"year":2000,"finding":"SRL300 (SRRM2) protein was cloned as a binding protein for the 5'-noncoding sequence of ATBF1 mRNA; it contains a unique RNA-binding region and two large RS domains with multiple phosphorylation sites, and is detected in both human and rat cells.","method":"cDNA cloning, sequence analysis, immunodetection in human and rat cells","journal":"Biochimica et biophysica acta","confidence":"Low","confidence_rationale":"Tier 3 / Weak — initial cloning and characterization, single method, no functional follow-up","pmids":["11004489"],"is_preprint":false},{"year":2021,"finding":"SRRM2, normally a nuclear speckle scaffold protein, is mislocalized to cytoplasmic lesions (neurofibrillary tangles) in Alzheimer's disease brain tissue and in transgenic tauopathy mice, with mislocalization severity correlating with pathological tau deposition. This identifies pathological tau as a driver of ectopic cytoplasmic accumulation of SRRM2.","method":"Immunohistochemistry and immunofluorescence in human AD tissue and transgenic mouse brain, correlation with tau pathology staging","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment in human tissue and mouse model with tau-burden correlation, two independent biological systems","pmids":["34187600"],"is_preprint":false},{"year":2025,"finding":"A point mutation in SRRM2 associated with familial ALS causes loss of the protein-protein interaction between SRRM2 and the splicing factor ACIN1, and leads to widespread differential gene expression converging on dysregulation of synapse-associated pathways in a model cell line carrying the endogenous point mutation.","method":"Endogenous point mutation knock-in, co-immunoprecipitation (loss of ACIN1 interaction), transcriptomics (RNA-seq)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — endogenous mutation knock-in with co-IP and transcriptomics, preprint, single lab","pmids":[],"is_preprint":true},{"year":2025,"finding":"SRRM2 is a substrate/target of the nuclear speckle-localized kinase TAOK2: biochemical phosphoproteomics identifies SRRM2 (and SRRM1) as potential direct phosphorylation targets of TAOK2. TAOK2 knockdown perturbs speckle-resident SR proteins (including SRRM2-containing speckles) while leaving hnRNPs unperturbed, suggesting that TAOK2-mediated phosphorylation of SRRM2 plays a structural maintenance role at nuclear speckles.","method":"siRNA knockdown, cellular and biochemical phosphoproteomics, splicing and nuclear export transcriptomics, imaging of nuclear speckle integrity","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — phosphoproteomics identifying SRRM2 as potential substrate, indirect evidence, preprint, no direct kinase assay with SRRM2 shown","pmids":[],"is_preprint":true},{"year":2025,"finding":"Polyphosphate (polyP) directly interacts with SRRM2 (the NS core component), and polyP depletion disrupts nuclear speckle organization. Mechanistically, polyP acts as a physiological inhibitor of CLK3 kinase, preventing phosphorylation of SR proteins and thereby maintaining nuclear speckle stability.","method":"BAR (Biotinylation by Antibody Recognition) proximity labeling, polyP depletion experiments, imaging of nuclear speckle integrity, RNA-seq, CLK3 kinase inhibition assay","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proximity labeling for interaction, functional depletion for phenotype, preprint, single lab, indirect mechanistic link for CLK3","pmids":[],"is_preprint":true},{"year":2024,"finding":"In senescent cells, SRRM2 is repurposed to cluster CTCF into senescence-induced clusters (SICCs) at nuclear speckles, together with BANF1. The RNA-binding domain of SRRM2 directs CTCF clustering, and SICC disruption fully reverts senescence-associated alternative splicing patterns, demonstrating that SRRM2-mediated nuclear speckle reorganization sustains the senescence splicing program.","method":"Functional assays, super-resolution imaging, 3D genomics, computational modelling, domain deletion (SRRM2 RNA-binding domain)","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, domain-level functional evidence but mechanistic detail of direct SRRM2-CTCF interaction not fully established by in vitro assay","pmids":[],"is_preprint":true},{"year":2025,"finding":"Srrm2 haploinsufficiency in mice causes splicing dysregulation including reduction of SynGAP-γ isoform and mis-splicing of Agap3, reduced oligodendrocyte proportions in striatum, and decreased myelin-related gene expression. These AGAP3 splicing defects are conserved in human iPSC-derived neurons deficient in SRRM2.","method":"Srrm2+/- mouse model, single-nucleus RNA-seq, proteomics, human iPSC-derived neurons with SRRM2 depletion, EEG, behavioral assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function mouse model with transcriptomic/proteomic readouts validated in human iPSC neurons, single lab, multiple orthogonal methods","pmids":["42189682"],"is_preprint":false},{"year":2025,"finding":"SRRM2 modulates levels of S6K1 and S6K2 to activate the mTOR-S6K pathway in colorectal cancer: SRRM2 facilitates S6K2 expression by modulating alternative splicing, and enhances S6K1 protein stability by regulating the E3 ubiquitin ligase WWP2.","method":"SRRM2 knockdown/overexpression, alternative splicing analysis (RNA-seq), protein stability assays, ubiquitin ligase regulation assays, in vitro and in vivo CRC growth assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple functional assays with defined pathway placement (mTOR-S6K, WWP2), single lab","pmids":["39956864"],"is_preprint":false},{"year":2024,"finding":"The intrinsically disordered region (IDR) of SRRM2 is required for enlarging nuclear speckles in the presence of HIV capsid, and HIV-induced CPSF6 puncta fuse with nuclear speckles via the IDR of SRRM2.","method":"Genetic manipulation and depletion of SRRM2 IDR, live-cell imaging of CPSF6 puncta/speckle fusion, domain deletion experiments","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, domain deletion with imaging but limited mechanistic follow-up of direct IDR interaction","pmids":[],"is_preprint":true},{"year":2024,"finding":"Disruption of nuclear speckle integrity through SRRM2 downregulation promotes TDP-43 mislocalization from the nucleus and loss of TDP-43 splicing function.","method":"siRNA knockdown of SRRM2, TDP-43 localization imaging, cryptic exon splicing assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single method per finding, indirect mechanistic link between SRRM2 and TDP-43 function","pmids":[],"is_preprint":true},{"year":2020,"finding":"Srrm2 heterozygosity in embryonic stem cells induces loss of stemness, with coexistence of naive and formative pluripotency markers and changes in expression of SRF-regulated and differentiation-related genes. The earliest effects of Srrm2 heterozygosity are specific alternative splicing events on a small number of genes, followed by broader gene expression changes.","method":"Srrm2 heterozygous mouse ESC line, RNA interference, transcriptomics (RNA-seq), pluripotency marker immunofluorescence","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic model combined with RNAi and transcriptomics revealing ordered splicing-then-expression changes, single lab","pmids":["38656788"],"is_preprint":false}],"current_model":"SRRM2 (SRm300/Cwc21 ortholog) is a large serine/arginine-rich nuclear protein that functions as a core scaffold of nuclear speckles—together with SON—by driving liquid-liquid phase separation through its intrinsically disordered RS domains, which oligomerize and mediate both homotypic and heterotypic RNA-protein coacervation; as a bona fide splicing factor, SRRM2 docks directly to Prp8 and Snu114 at the catalytic center of the spliceosome (conserved from yeast Cwc21p), promotes inclusion of cassette exons with weak splice sites, regulates specific alternative splicing programs (including FES, MUC1, S6K2, AGAP3, and SynGAP isoforms), stabilizes S6K1 protein via regulation of the E3 ligase WWP2, interacts with arginyl-tRNA synthetase to couple metabolic arginine sensing to splicing, and its mislocalization to the cytoplasm in tauopathy and disruption of nuclear speckle integrity impair downstream splicing and RNA processing functions."},"narrative":{"mechanistic_narrative":"SRRM2 is a large serine/arginine-rich nuclear protein that serves, together with SON, as a core structural scaffold of nuclear speckles, where its intrinsically disordered RS domains drive liquid-liquid phase separation through homotypic oligomerization and non-selective heterotypic protein-RNA coacervation [PMID:33095160, PMID:35929045, PMID:38381607]. SON and SRRM2 form immiscible multiphases that subcompartmentalize speckles and independently regulate distinct alternative splicing programs, with serine residues within the RS domains specifically tuning condensate liquidity [PMID:38381607]. As a splicing factor, SRRM2 docks directly to the core U5 snRNP proteins Prp8 and Snu114 at the spliceosome catalytic center—a function conserved from its yeast ortholog Cwc21p, which acts at or before the first catalytic step and contributes to splicing fidelity through interaction with Isy1p [PMID:19854871, PMID:19789211]; it cooperates with cactin and DHX8 for efficient splicing of thousands of transcripts and for sister chromatid cohesion [PMID:28062851]. SRRM2 promotes inclusion of cassette exons bearing short introns and weak splice sites and shapes specific isoform programs, including FES, MUC1, SynGAP, and AGAP3 [PMID:35929045, PMID:42189682], and in colorectal cancer it activates mTOR-S6K signaling by splicing-dependent control of S6K2 and by stabilizing S6K1 via the E3 ligase WWP2 [PMID:39956864]. SRRM2 couples cellular state to splicing: nuclear arginyl-tRNA synthetase associates with SRRM2 to link arginine availability to splice-site usage [PMID:37059883], and SRRM2-dependent speckle reorganization sustains senescence and pluripotency-associated splicing programs [PMID:38656788]. A germline S346F variant increases exon inclusion in carriers [PMID:26135620], and pathological tau drives mislocalization of SRRM2 from nuclear speckles into cytoplasmic neurofibrillary tangles in Alzheimer's disease, linking speckle disruption to impaired RNA processing in tauopathy [PMID:34187600].","teleology":[{"year":2000,"claim":"Initial cloning established SRRM2 as an RNA-associated protein with a unique RNA-binding region and two large phosphorylation-rich RS domains, defining the architecture that would later prove central to its function.","evidence":"cDNA cloning and sequence analysis as an ATBF1 mRNA 5'-UTR binding protein (SRL300) in human and rat cells","pmids":["11004489"],"confidence":"Low","gaps":["No functional follow-up of the ATBF1 mRNA interaction","RS domain function not tested"]},{"year":2003,"claim":"Early interaction screens placed SRRM2 in nuclear-speckle multiprotein complexes and connected it to viral transcriptional control, hinting at a broad role in nuclear gene-expression machinery.","evidence":"Yeast two-hybrid and co-IP with Pinin and SR-rich proteins in corneal/HEK cells; co-IP, reporter, and siRNA showing coactivation of HTLV-1 Tax transactivation","pmids":["14578391","12941912"],"confidence":"Medium","gaps":["Mechanism linking complex membership to splicing not defined","Tax coactivation pathway not connected to speckle scaffolding"]},{"year":2009,"claim":"Yeast genetics resolved how SRRM2 engages the splicing machinery, showing its ortholog docks directly onto core U5 snRNP proteins at the spliceosome catalytic center and acts at the first catalytic step.","evidence":"Direct binding/cross-linking, genetic epistasis, and TAP-MS in S. cerevisiae Cwc21p, with demonstrated human SRm300 orthology; interactions with Prp8p, Snu114p, and Isy1p","pmids":["19854871","19789211"],"confidence":"High","gaps":["Human SRRM2 docking inferred by orthology, not directly mapped structurally in human spliceosome","Catalytic contribution vs. scaffolding not separated"]},{"year":2013,"claim":"Work in C. elegans suggested SRRM2 is recruited to chromatin co-transcriptionally and influences RNA Pol II, expanding its role beyond the spliceosome to the transcription interface.","evidence":"RNAi, genetic epistasis, ChIP-Seq, and co-IP with RNAPII for the ortholog RSR-2","pmids":["23754964"],"confidence":"Medium","gaps":["Splicing-independent chromatin role not confirmed in human SRRM2","Mechanism of RNAPII phosphorylation modulation unknown"]},{"year":2017,"claim":"Identification of the cactin-SRRM2-DHX8 complex linked SRRM2 splicing activity to a concrete cell-biological outcome—efficient sororin splicing and sister chromatid cohesion.","evidence":"Co-IP, siRNA depletion, RNA-seq, and chromosome segregation assays in human cells","pmids":["28062851"],"confidence":"Medium","gaps":["Direct vs. indirect SRRM2-cactin contact not resolved","Single lab"]},{"year":2020,"claim":"Reciprocal genetic depletion established SRRM2 and SON as the essential dual scaffold of nuclear speckles and corrected the long-standing misattribution of the SC35 marker, reframing SRRM2 as a structural organizer.","evidence":"siRNA co-depletion, CRISPR IDR deletion, immunofluorescence, immunoblot, proteomics; plus ESC Srrm2 heterozygosity transcriptomics showing splicing-first then expression effects","pmids":["33095160","38656788"],"confidence":"High","gaps":["IDR sequence features driving scaffolding not fully dissected at this stage","Relationship between scaffold role and individual splicing targets unresolved"]},{"year":2024,"claim":"In vitro reconstitution and domain swaps defined the biophysical basis of speckle organization, showing SRRM2 and SON form immiscible multiphases and that RS-domain serines fine-tune condensate liquidity while controlling distinct splicing targets.","evidence":"Super-resolution imaging, FRAP, in vitro phase separation, domain swap/mutagenesis, and RNA-seq","pmids":["38381607"],"confidence":"High","gaps":["RNA species driving heterotypic coacervation not identified","How liquidity tuning maps to specific splice choices unclear"]},{"year":2023,"claim":"Coupling of SRRM2 to nuclear arginyl-tRNA synthetase showed metabolic state (arginine availability) can be transduced into altered splice-site usage, giving SRRM2 a signal-integration role.","evidence":"Co-IP, co-localization imaging, arginine depletion, RNA-seq splice-site analysis, and immunopeptidome assays","pmids":["37059883"],"confidence":"Medium","gaps":["Mechanism by which ArgRS alters SRRM2 condensate behavior not defined","Direct vs. indirect functional coupling unresolved"]},{"year":2025,"claim":"Loss-of-function models tied SRRM2 dosage to specific neural splicing programs and to oncogenic signaling, defining concrete downstream effectors of SRRM2-dependent splicing.","evidence":"Srrm2+/- mice with snRNA-seq/proteomics validated in human iPSC neurons (SynGAP, Agap3, myelin); CRC SRRM2 perturbation linking S6K2 splicing and WWP2-mediated S6K1 stabilization to mTOR-S6K","pmids":["42189682","39956864"],"confidence":"Medium","gaps":["Whether neural and cancer programs share a common splicing logic unknown","Direct WWP2 regulation mechanism not detailed"]},{"year":2025,"claim":"Disease-linked findings connected SRRM2 dysfunction to neurodegeneration through speckle disruption, including tau-driven cytoplasmic mislocalization and a familial ALS mutation that severs the SRRM2-ACIN1 interaction.","evidence":"IHC/IF in AD tissue and tauopathy mice; endogenous ALS point-mutation knock-in with co-IP (loss of ACIN1) and RNA-seq (preprint)","pmids":["34187600"],"confidence":"Medium","gaps":["Causal direction between speckle disruption and tau pathology not fully established","ALS finding is a single-lab preprint awaiting peer review"]},{"year":null,"claim":"How upstream kinases and small-molecule cofactors regulate SRRM2 condensate state, and how that regulation selects specific splicing outcomes across tissues, remains unresolved.","evidence":"Preprint phosphoproteomics implicating TAOK2 and polyP/CLK3 in speckle maintenance lack direct in vitro kinase/binding confirmation","pmids":[],"confidence":"Low","gaps":["No direct kinase assay on SRRM2 demonstrated","Quantitative link between phosphorylation state and target selection missing","Generalizability across cell types untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[11,1,16]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,8]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5,9]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,3,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8]}],"complexes":["nuclear speckle","spliceosome (NTC-related/U5 snRNP-associated)","cactin-SRRM2-DHX8 complex"],"partners":["SON","PRPF8","SNRNP200","PININ","CACTIN","ACIN1","RARS","ISY1"],"other_free_text":[]}},"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; CACTIN","url":"https://www.omim.org/entry/618536"},{"mim_id":"616653","title":"PNN-INTERACTING SERINE/ARGININE-RICH PROTEIN; PNISR","url":"https://www.omim.org/entry/616653"},{"mim_id":"613103","title":"SERINE/ARGININE REPETITIVE MATRIX PROTEIN 4; SRRM4","url":"https://www.omim.org/entry/613103"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nuclear speckles","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SRRM2"},"hgnc":{"alias_symbol":["SRm300","SRL300","KIAA0324","Cwc21"],"prev_symbol":[]},"alphafold":{"accession":"Q9UQ35","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UQ35","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UQ35-3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UQ35-3-F1-predicted_aligned_error_v6.png","plddt_mean":57.22},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRRM2","jax_strain_url":"https://www.jax.org/strain/search?query=SRRM2"},"sequence":{"accession":"Q9UQ35","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UQ35.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UQ35/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UQ35"}},"corpus_meta":[{"pmid":"33095160","id":"PMC_33095160","title":"SON and SRRM2 are essential for nuclear speckle 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depletion of SON alone causes partial disassembly, but co-depletion of SON and SRRM2, or depletion of SON in cells where SRRM2's intrinsically disordered regions (IDRs) are genetically deleted, causes near-complete dissolution of nuclear speckles. The SC35 monoclonal antibody, widely used as a nuclear speckle marker, was found to principally recognize SRRM2, not SRSF2.\",\n      \"method\": \"siRNA co-depletion, CRISPR-mediated IDR deletion, immunofluorescence, immunoblot, proteomics\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic depletion with multiple orthogonal methods (siRNA, CRISPR deletion, imaging), rigorous controls, replicated across cell lines\",\n      \"pmids\": [\"33095160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SRRM2 forms biomolecular condensates consistent with liquid-liquid phase separation (spherical shape, dynamic rearrangement, coalescence, concentration dependence confirmed in vitro). SRRM2 organizes nuclear speckles throughout the cell cycle. SRRM2 deficiency causes skipping of cassette exons with short introns and weak splice sites. In THP-1 myeloid-like cells, SRRM2 depletion compromises cell viability, upregulates differentiation markers, and sensitizes cells to anti-leukemia drugs. SRRM2 induces a FES splice isoform that attenuates innate inflammatory responses and MUC1 isoforms with oncogenic shedding properties.\",\n      \"method\": \"EGFP-SRRM2 knock-in HEK293T cells, live-cell imaging, in vitro phase separation assay, RNA-seq after SRRM2 depletion, cell viability assays, drug sensitivity assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (live imaging, in vitro reconstitution, transcriptomics, functional cellular assays) in a single focused study\",\n      \"pmids\": [\"35929045\"],\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 drives nuclear speckle subcompartmentalization via homotypic interaction (through RS domain oligomerization) and heterotypic non-selective protein-RNA coacervation-driven phase separation. Serine residues within the RS domains play an irreplaceable role in fine-tuning nuclear speckle liquidity; RS domains can be functionally replaced by synthetic oligomerizable modules for structural but not liquidity roles.\",\n      \"method\": \"Super-resolution imaging, FRAP, in vitro phase separation, domain swap/mutagenesis, RNA-seq, cell-based condensate assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution combined with domain mutagenesis and live-cell imaging, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"38381607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Yeast Cwc21p (ortholog of human SRm300/SRRM2) binds directly to two core spliceosomal proteins, Prp8p and Snu114p (U5 snRNP), making it the first NTC-related protein known to dock directly to U5 snRNP proteins. The conserved cwf21 domain in Cwc21p is the Prp8p binding site. Cwc21p and Isy1p have related functions at or prior to the first catalytic step of splicing. Human SRm300/SRRM2 is a functional ortholog of Cwc21p, also directly interacting with Prp8p and Snu114p.\",\n      \"method\": \"Direct binding assays, chemical cross-linking, proteomic analysis of the SCwid domain, genetic interaction (suppressor/synthetic lethality), co-immunoprecipitation\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding assays with cross-linking footprinting, genetic epistasis, and demonstration of human SRm300 functional orthology in a single rigorous study\",\n      \"pmids\": [\"19854871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Yeast Cwc21p (ortholog of SRm300/SRRM2) shows strong genetic, physical, and functional interactions with Isy1p (implicated in the first catalytic step of splicing and splicing fidelity), and associates with spliceosomal complexes, supporting a role for Cwc21/SRm300 in spliceosome activation and splicing fidelity.\",\n      \"method\": \"Quantitative genetic interaction mapping, tandem affinity purification mass spectrometry, microarray profiling\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TAP-MS and genetic interaction mapping, single lab, multiple complementary approaches\",\n      \"pmids\": [\"19789211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SRRM2 (SRm300) physically interacts with Pinin (Pnn/DRS/memA) at the C-terminus of Pinin, and co-immunoprecipitates and co-localizes with Pinin and other SR-rich proteins (SRp75, SRrp130) in nuclear speckles in corneal epithelial cells, suggesting participation in a multiprotein nuclear complex involved in pre-mRNA processing.\",\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 3 / Moderate — yeast two-hybrid and co-IP, two orthogonal methods, single lab\",\n      \"pmids\": [\"14578391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SRRM2 (as TAXREB803/SRL300) interacts with HTLV-1 Tax oncoprotein, co-immunoprecipitates with Tax, co-localizes with Tax by indirect immunofluorescence, enhances Tax-dependent transcription and CREB binding to TxRE. Knockdown of TAXREB803 by siRNA dramatically decreases Tax transactivation of the HTLV-1 LTR, identifying SRRM2 as a transcriptional coactivator for Tax.\",\n      \"method\": \"Co-immunoprecipitation, indirect immunofluorescence, luciferase reporter assay, siRNA knockdown\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP, co-localization, reporter assay, and siRNA knockdown in a single lab with multiple methods\",\n      \"pmids\": [\"12941912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RSR-2, the C. elegans ortholog of SRm300/SRRM2, is essential for viability and acts within the germline sex determination pathway (genetic epistasis). RSR-2 colocalizes with DNA in germline nuclei and co-precipitates with chromatin, with a ChIP-Seq profile similar to RNA Polymerase II. RSR-2 recruitment to chromatin is splicing-independent. RSR-2 interacts with RNAPII and affects RNAPII phosphorylation states. Strongest interacting partners identified by proteomics are PRP-8 and PRP-19.\",\n      \"method\": \"RNAi, genetic epistasis analysis, transcriptomics, ChIP-Seq, co-immunoprecipitation with RNAPII, proteomic analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-Seq, co-IP, genetic epistasis in C. elegans ortholog, single lab, multiple methods\",\n      \"pmids\": [\"23754964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Human cactin physically and functionally interacts with SRRM2 (co-immunoprecipitation), and this complex (along with DHX8) is required for efficient pre-mRNA splicing of thousands of transcripts and for sister chromatid cohesion. Cactin depletion impairs splicing of sororin (CDCA5) pre-mRNA, causing premature sister chromatid separation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA depletion, RNA-seq splicing analysis, cell biology (chromosome segregation assay)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP plus functional depletion with defined cellular phenotype, single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"28062851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nuclear arginyl-tRNA synthetase (ArgRS) interacts and co-localizes with SRRM2. During arginine depletion (as occurs in inflammation), nuclear ArgRS levels decrease, which correlates with changes in condensate-like nuclear trafficking of SRRM2 and altered splice-site usage in specific genes, leading to different protein isoforms that alter cellular metabolism and peptide presentation to immune cells.\",\n      \"method\": \"Co-immunoprecipitation, co-localization by imaging, arginine depletion experiments, RNA-seq splice site analysis, metabolic and immunopeptidome assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and co-localization with functional splice-site analysis, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"37059883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The germline missense variant S346F in SRRM2 causes a higher ratio of exon inclusion in leukocytes of carriers compared to controls (RNA-seq and experimental validation of 7 exons), consistent with altered alternative splicing activity of SRRM2 due to this mutation.\",\n      \"method\": \"RNA-seq in human leukocytes from variant carriers vs. controls, experimental validation of specific exon inclusion events by RT-PCR\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq with experimental validation of splicing changes in human carriers, single lab, multiple orthogonal validations\",\n      \"pmids\": [\"26135620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SRL300 (SRRM2) protein was cloned as a binding protein for the 5'-noncoding sequence of ATBF1 mRNA; it contains a unique RNA-binding region and two large RS domains with multiple phosphorylation sites, and is detected in both human and rat cells.\",\n      \"method\": \"cDNA cloning, sequence analysis, immunodetection in human and rat cells\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — initial cloning and characterization, single method, no functional follow-up\",\n      \"pmids\": [\"11004489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRRM2, normally a nuclear speckle scaffold protein, is mislocalized to cytoplasmic lesions (neurofibrillary tangles) in Alzheimer's disease brain tissue and in transgenic tauopathy mice, with mislocalization severity correlating with pathological tau deposition. This identifies pathological tau as a driver of ectopic cytoplasmic accumulation of SRRM2.\",\n      \"method\": \"Immunohistochemistry and immunofluorescence in human AD tissue and transgenic mouse brain, correlation with tau pathology staging\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment in human tissue and mouse model with tau-burden correlation, two independent biological systems\",\n      \"pmids\": [\"34187600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A point mutation in SRRM2 associated with familial ALS causes loss of the protein-protein interaction between SRRM2 and the splicing factor ACIN1, and leads to widespread differential gene expression converging on dysregulation of synapse-associated pathways in a model cell line carrying the endogenous point mutation.\",\n      \"method\": \"Endogenous point mutation knock-in, co-immunoprecipitation (loss of ACIN1 interaction), transcriptomics (RNA-seq)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — endogenous mutation knock-in with co-IP and transcriptomics, preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SRRM2 is a substrate/target of the nuclear speckle-localized kinase TAOK2: biochemical phosphoproteomics identifies SRRM2 (and SRRM1) as potential direct phosphorylation targets of TAOK2. TAOK2 knockdown perturbs speckle-resident SR proteins (including SRRM2-containing speckles) while leaving hnRNPs unperturbed, suggesting that TAOK2-mediated phosphorylation of SRRM2 plays a structural maintenance role at nuclear speckles.\",\n      \"method\": \"siRNA knockdown, cellular and biochemical phosphoproteomics, splicing and nuclear export transcriptomics, imaging of nuclear speckle integrity\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — phosphoproteomics identifying SRRM2 as potential substrate, indirect evidence, preprint, no direct kinase assay with SRRM2 shown\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Polyphosphate (polyP) directly interacts with SRRM2 (the NS core component), and polyP depletion disrupts nuclear speckle organization. Mechanistically, polyP acts as a physiological inhibitor of CLK3 kinase, preventing phosphorylation of SR proteins and thereby maintaining nuclear speckle stability.\",\n      \"method\": \"BAR (Biotinylation by Antibody Recognition) proximity labeling, polyP depletion experiments, imaging of nuclear speckle integrity, RNA-seq, CLK3 kinase inhibition assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proximity labeling for interaction, functional depletion for phenotype, preprint, single lab, indirect mechanistic link for CLK3\",\n      \"pmids\": [],\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) at nuclear speckles, together with BANF1. The RNA-binding domain of SRRM2 directs CTCF clustering, and SICC disruption fully reverts senescence-associated alternative splicing patterns, demonstrating that SRRM2-mediated nuclear speckle reorganization sustains the senescence splicing program.\",\n      \"method\": \"Functional assays, super-resolution imaging, 3D genomics, computational modelling, domain deletion (SRRM2 RNA-binding domain)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, domain-level functional evidence but mechanistic detail of direct SRRM2-CTCF interaction not fully established by in vitro assay\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Srrm2 haploinsufficiency in mice causes splicing dysregulation including reduction of SynGAP-γ isoform and mis-splicing of Agap3, reduced oligodendrocyte proportions in striatum, and decreased myelin-related gene expression. These AGAP3 splicing defects are conserved in human iPSC-derived neurons deficient in SRRM2.\",\n      \"method\": \"Srrm2+/- mouse model, single-nucleus RNA-seq, proteomics, human iPSC-derived neurons with SRRM2 depletion, EEG, behavioral assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function mouse model with transcriptomic/proteomic readouts validated in human iPSC neurons, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"42189682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SRRM2 modulates levels of S6K1 and S6K2 to activate the mTOR-S6K pathway in colorectal cancer: SRRM2 facilitates S6K2 expression by modulating alternative splicing, and enhances S6K1 protein stability by regulating the E3 ubiquitin ligase WWP2.\",\n      \"method\": \"SRRM2 knockdown/overexpression, alternative splicing analysis (RNA-seq), protein stability assays, ubiquitin ligase regulation assays, in vitro and in vivo CRC growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple functional assays with defined pathway placement (mTOR-S6K, WWP2), single lab\",\n      \"pmids\": [\"39956864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The intrinsically disordered region (IDR) of SRRM2 is required for enlarging nuclear speckles in the presence of HIV capsid, and HIV-induced CPSF6 puncta fuse with nuclear speckles via the IDR of SRRM2.\",\n      \"method\": \"Genetic manipulation and depletion of SRRM2 IDR, live-cell imaging of CPSF6 puncta/speckle fusion, domain deletion experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, domain deletion with imaging but limited mechanistic follow-up of direct IDR interaction\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Disruption of nuclear speckle integrity through SRRM2 downregulation promotes TDP-43 mislocalization from the nucleus and loss of TDP-43 splicing function.\",\n      \"method\": \"siRNA knockdown of SRRM2, TDP-43 localization imaging, cryptic exon splicing assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single method per finding, indirect mechanistic link between SRRM2 and TDP-43 function\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Srrm2 heterozygosity in embryonic stem cells induces loss of stemness, with coexistence of naive and formative pluripotency markers and changes in expression of SRF-regulated and differentiation-related genes. The earliest effects of Srrm2 heterozygosity are specific alternative splicing events on a small number of genes, followed by broader gene expression changes.\",\n      \"method\": \"Srrm2 heterozygous mouse ESC line, RNA interference, transcriptomics (RNA-seq), pluripotency marker immunofluorescence\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic model combined with RNAi and transcriptomics revealing ordered splicing-then-expression changes, single lab\",\n      \"pmids\": [\"38656788\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SRRM2 (SRm300/Cwc21 ortholog) is a large serine/arginine-rich nuclear protein that functions as a core scaffold of nuclear speckles—together with SON—by driving liquid-liquid phase separation through its intrinsically disordered RS domains, which oligomerize and mediate both homotypic and heterotypic RNA-protein coacervation; as a bona fide splicing factor, SRRM2 docks directly to Prp8 and Snu114 at the catalytic center of the spliceosome (conserved from yeast Cwc21p), promotes inclusion of cassette exons with weak splice sites, regulates specific alternative splicing programs (including FES, MUC1, S6K2, AGAP3, and SynGAP isoforms), stabilizes S6K1 protein via regulation of the E3 ligase WWP2, interacts with arginyl-tRNA synthetase to couple metabolic arginine sensing to splicing, and its mislocalization to the cytoplasm in tauopathy and disruption of nuclear speckle integrity impair downstream splicing and RNA processing functions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SRRM2 is a large serine/arginine-rich nuclear protein that serves, together with SON, as a core structural scaffold of nuclear speckles, where its intrinsically disordered RS domains drive liquid-liquid phase separation through homotypic oligomerization and non-selective heterotypic protein-RNA coacervation [#0, #1, #2]. SON and SRRM2 form immiscible multiphases that subcompartmentalize speckles and independently regulate distinct alternative splicing programs, with serine residues within the RS domains specifically tuning condensate liquidity [#2]. As a splicing factor, SRRM2 docks directly to the core U5 snRNP proteins Prp8 and Snu114 at the spliceosome catalytic center—a function conserved from its yeast ortholog Cwc21p, which acts at or before the first catalytic step and contributes to splicing fidelity through interaction with Isy1p [#3, #4]; it cooperates with cactin and DHX8 for efficient splicing of thousands of transcripts and for sister chromatid cohesion [#8]. SRRM2 promotes inclusion of cassette exons bearing short introns and weak splice sites and shapes specific isoform programs, including FES, MUC1, SynGAP, and AGAP3 [#1, #17], and in colorectal cancer it activates mTOR-S6K signaling by splicing-dependent control of S6K2 and by stabilizing S6K1 via the E3 ligase WWP2 [#18]. SRRM2 couples cellular state to splicing: nuclear arginyl-tRNA synthetase associates with SRRM2 to link arginine availability to splice-site usage [#9], and SRRM2-dependent speckle reorganization sustains senescence and pluripotency-associated splicing programs [#21]. A germline S346F variant increases exon inclusion in carriers [#10], and pathological tau drives mislocalization of SRRM2 from nuclear speckles into cytoplasmic neurofibrillary tangles in Alzheimer's disease, linking speckle disruption to impaired RNA processing in tauopathy [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Initial cloning established SRRM2 as an RNA-associated protein with a unique RNA-binding region and two large phosphorylation-rich RS domains, defining the architecture that would later prove central to its function.\",\n      \"evidence\": \"cDNA cloning and sequence analysis as an ATBF1 mRNA 5'-UTR binding protein (SRL300) in human and rat cells\",\n      \"pmids\": [\"11004489\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional follow-up of the ATBF1 mRNA interaction\", \"RS domain function not tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Early interaction screens placed SRRM2 in nuclear-speckle multiprotein complexes and connected it to viral transcriptional control, hinting at a broad role in nuclear gene-expression machinery.\",\n      \"evidence\": \"Yeast two-hybrid and co-IP with Pinin and SR-rich proteins in corneal/HEK cells; co-IP, reporter, and siRNA showing coactivation of HTLV-1 Tax transactivation\",\n      \"pmids\": [\"14578391\", \"12941912\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking complex membership to splicing not defined\", \"Tax coactivation pathway not connected to speckle scaffolding\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Yeast genetics resolved how SRRM2 engages the splicing machinery, showing its ortholog docks directly onto core U5 snRNP proteins at the spliceosome catalytic center and acts at the first catalytic step.\",\n      \"evidence\": \"Direct binding/cross-linking, genetic epistasis, and TAP-MS in S. cerevisiae Cwc21p, with demonstrated human SRm300 orthology; interactions with Prp8p, Snu114p, and Isy1p\",\n      \"pmids\": [\"19854871\", \"19789211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human SRRM2 docking inferred by orthology, not directly mapped structurally in human spliceosome\", \"Catalytic contribution vs. scaffolding not separated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Work in C. elegans suggested SRRM2 is recruited to chromatin co-transcriptionally and influences RNA Pol II, expanding its role beyond the spliceosome to the transcription interface.\",\n      \"evidence\": \"RNAi, genetic epistasis, ChIP-Seq, and co-IP with RNAPII for the ortholog RSR-2\",\n      \"pmids\": [\"23754964\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Splicing-independent chromatin role not confirmed in human SRRM2\", \"Mechanism of RNAPII phosphorylation modulation unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of the cactin-SRRM2-DHX8 complex linked SRRM2 splicing activity to a concrete cell-biological outcome—efficient sororin splicing and sister chromatid cohesion.\",\n      \"evidence\": \"Co-IP, siRNA depletion, RNA-seq, and chromosome segregation assays in human cells\",\n      \"pmids\": [\"28062851\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect SRRM2-cactin contact not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reciprocal genetic depletion established SRRM2 and SON as the essential dual scaffold of nuclear speckles and corrected the long-standing misattribution of the SC35 marker, reframing SRRM2 as a structural organizer.\",\n      \"evidence\": \"siRNA co-depletion, CRISPR IDR deletion, immunofluorescence, immunoblot, proteomics; plus ESC Srrm2 heterozygosity transcriptomics showing splicing-first then expression effects\",\n      \"pmids\": [\"33095160\", \"38656788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"IDR sequence features driving scaffolding not fully dissected at this stage\", \"Relationship between scaffold role and individual splicing targets unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"In vitro reconstitution and domain swaps defined the biophysical basis of speckle organization, showing SRRM2 and SON form immiscible multiphases and that RS-domain serines fine-tune condensate liquidity while controlling distinct splicing targets.\",\n      \"evidence\": \"Super-resolution imaging, FRAP, in vitro phase separation, domain swap/mutagenesis, and RNA-seq\",\n      \"pmids\": [\"38381607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA species driving heterotypic coacervation not identified\", \"How liquidity tuning maps to specific splice choices unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Coupling of SRRM2 to nuclear arginyl-tRNA synthetase showed metabolic state (arginine availability) can be transduced into altered splice-site usage, giving SRRM2 a signal-integration role.\",\n      \"evidence\": \"Co-IP, co-localization imaging, arginine depletion, RNA-seq splice-site analysis, and immunopeptidome assays\",\n      \"pmids\": [\"37059883\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ArgRS alters SRRM2 condensate behavior not defined\", \"Direct vs. indirect functional coupling unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Loss-of-function models tied SRRM2 dosage to specific neural splicing programs and to oncogenic signaling, defining concrete downstream effectors of SRRM2-dependent splicing.\",\n      \"evidence\": \"Srrm2+/- mice with snRNA-seq/proteomics validated in human iPSC neurons (SynGAP, Agap3, myelin); CRC SRRM2 perturbation linking S6K2 splicing and WWP2-mediated S6K1 stabilization to mTOR-S6K\",\n      \"pmids\": [\"42189682\", \"39956864\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether neural and cancer programs share a common splicing logic unknown\", \"Direct WWP2 regulation mechanism not detailed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Disease-linked findings connected SRRM2 dysfunction to neurodegeneration through speckle disruption, including tau-driven cytoplasmic mislocalization and a familial ALS mutation that severs the SRRM2-ACIN1 interaction.\",\n      \"evidence\": \"IHC/IF in AD tissue and tauopathy mice; endogenous ALS point-mutation knock-in with co-IP (loss of ACIN1) and RNA-seq (preprint)\",\n      \"pmids\": [\"34187600\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal direction between speckle disruption and tau pathology not fully established\", \"ALS finding is a single-lab preprint awaiting peer review\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How upstream kinases and small-molecule cofactors regulate SRRM2 condensate state, and how that regulation selects specific splicing outcomes across tissues, remains unresolved.\",\n      \"evidence\": \"Preprint phosphoproteomics implicating TAOK2 and polyP/CLK3 in speckle maintenance lack direct in vitro kinase/binding confirmation\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct kinase assay on SRRM2 demonstrated\", \"Quantitative link between phosphorylation state and target selection missing\", \"Generalizability across cell types untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [11, 1, 16]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 3, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\n      \"nuclear speckle\",\n      \"spliceosome (NTC-related/U5 snRNP-associated)\",\n      \"cactin-SRRM2-DHX8 complex\"\n    ],\n    \"partners\": [\n      \"SON\",\n      \"PRPF8\",\n      \"SNRNP200\",\n      \"Pinin\",\n      \"CACTIN\",\n      \"ACIN1\",\n      \"RARS\",\n      \"ISY1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}