{"gene":"RSRC1","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":2005,"finding":"SRrp53 (RSRC1) is a novel SR-related protein required for the second step of pre-mRNA splicing: immunodepletion of SRrp53 from HeLa nuclear extracts blocks the second step of splicing, and recombinant SRrp53 restores splicing activity. SRrp53 interacts with the mouse ortholog of yeast U1 snRNP-specific protein Luc7p, the U2AF65-related factor HCC1, members of the SR protein family, and U2AF35 (shown by yeast two-hybrid and in cell extracts). SRrp53 also regulates alternative splicing in a concentration-dependent manner. The protein localizes to nuclear speckles.","method":"Immunodepletion/reconstitution of splicing in HeLa nuclear extracts; yeast two-hybrid; co-immunoprecipitation from cell extracts; gene trap screen for nuclear speckle localization","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of splicing activity with immunodepletion and recombinant protein rescue, supported by two orthogonal protein-interaction methods (yeast two-hybrid + co-IP), single lab","pmids":["15798186"],"is_preprint":false},{"year":2015,"finding":"RSRC1 interacts with estrogen receptor β (ERβ) and promotes PIAS1-mediated SUMOylation of ERβ; SUMOylation of RSRC1 itself is required for this regulatory activity. Through this mechanism RSRC1 represses ERβ transcriptional activity.","method":"Co-immunoprecipitation; SUMOylation assays; transcriptional reporter assays; mutagenesis of SUMO sites on RSRC1","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional transcriptional assay and mutagenesis, single lab, multiple orthogonal methods","pmids":["25937118"],"is_preprint":false},{"year":2018,"finding":"Loss-of-function RSRC1 mutation (causing nonsense-mediated mRNA decay) in patients causes autosomal recessive intellectual disability, aberrant behaviour, hypotonia, and mild facial dysmorphism. shRNA-mediated silencing in SH-SY5Y cells demonstrates RSRC1 has a role in alternative splicing and transcription regulation. RSRC1 loss leads to downregulation of IGFBP3 (9.6-fold) in patient-derived iPSC-differentiated neural progenitor cells. Protein-protein interaction network modelling identified intermediate interactions mediating gene-specific differential expression.","method":"Homozygosity mapping; whole exome sequencing; RT-PCR (NMD confirmation in patient fibroblasts); shRNA lentiviral silencing and overexpression in SH-SY5Y cells; transcriptome profiling; iPSC differentiation to neural progenitor cells","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function in patient cells confirmed by NMD, functional rescue/silencing experiments in neuronal cell line with transcriptome readout, and patient iPSC-derived NPC validation; multiple orthogonal methods across independent cell systems","pmids":["29522154"],"is_preprint":false},{"year":2019,"finding":"RSRC1 knockdown in gastric cancer cells promotes proliferation and migration, and decreases PTEN protein and mRNA expression, indicating RSRC1 suppresses gastric cancer cell growth at least partly by maintaining PTEN expression.","method":"siRNA knockdown; Cell Counting Kit-8 proliferation assay; EdU incorporation assay; Transwell migration assay; Western blot and RT-qPCR for PTEN","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined cellular phenotype and molecular readout (PTEN), single lab, multiple functional assays but no rescue or epistasis experiment","pmids":["31257492"],"is_preprint":false},{"year":2025,"finding":"RNAi knockdown of spch-2, the C. elegans ortholog of RSRC1, produces significant and reproducible lifespan extension in C. elegans, identifying RSRC1 as an evolutionarily conserved driver of aging.","method":"Post-developmental RNA interference in C. elegans; lifespan assay (two independent trials, ~100 animals per genotype per trial)","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with replicated quantitative lifespan phenotype in a model organism ortholog; functional relevance to canonical mammalian RSRC1 is inferred by orthology","pmids":["41078088"],"is_preprint":false}],"current_model":"RSRC1 (SRrp53) is an SR-related nuclear protein that localizes to nuclear speckles, directly participates in both constitutive and alternative pre-mRNA splicing (required for the second catalytic step), interacts with spliceosomal components (Luc7p ortholog, HCC1, SR proteins, U2AF35/U2AF65), regulates transcription (including PTEN and IGFBP3 expression), and modulates ERβ transcriptional activity by promoting PIAS1-dependent ERβ SUMOylation in a manner dependent on RSRC1's own SUMOylation; loss of RSRC1 function in humans causes intellectual disability through aberrant splicing and transcription, and its C. elegans ortholog knockdown extends lifespan."},"narrative":{"mechanistic_narrative":"RSRC1 (SRrp53) is an SR-related nuclear protein that couples pre-mRNA splicing to transcriptional regulation and is essential for normal neurodevelopment [PMID:15798186, PMID:29522154]. In nuclear speckles it acts as a splicing factor specifically required for the second catalytic step of pre-mRNA splicing, functioning through interactions with the Luc7p ortholog, the U2AF65-related factor HCC1, SR-family proteins, and U2AF35, and it modulates alternative splice-site choice in a concentration-dependent manner [PMID:15798186]. Beyond constitutive splicing, RSRC1 regulates gene expression: it represses estrogen receptor β transcriptional activity by promoting PIAS1-dependent SUMOylation of ERβ in a manner that itself depends on RSRC1 SUMOylation [PMID:25937118], and it sustains expression of targets including PTEN and IGFBP3 [PMID:29522154, PMID:31257492]. Loss-of-function RSRC1 mutations that trigger nonsense-mediated decay cause autosomal recessive intellectual disability with hypotonia and mild dysmorphism, linked to aberrant splicing and transcription in patient-derived neural progenitors [PMID:29522154].","teleology":[{"year":2005,"claim":"Established that RSRC1/SRrp53 is a functional splicing factor by defining its specific requirement in the second catalytic step and its spliceosomal interaction network, answering whether the protein had a direct biochemical role in splicing.","evidence":"Immunodepletion/reconstitution of splicing in HeLa nuclear extracts with recombinant rescue, plus yeast two-hybrid and co-IP mapping of interactions with Luc7p ortholog, HCC1, SR proteins, and U2AF35","pmids":["15798186"],"confidence":"High","gaps":["Structural basis of second-step participation not resolved","No genome-wide map of endogenous splicing targets","Concentration-dependence of alternative splicing not linked to specific transcripts"]},{"year":2015,"claim":"Extended RSRC1 function from splicing to transcriptional control by showing it represses ERβ via SUMO-dependent regulation, revealing a SUMOylation-gated coregulator activity.","evidence":"Co-IP, SUMOylation assays, transcriptional reporters, and mutagenesis of RSRC1 SUMO sites","pmids":["25937118"],"confidence":"Medium","gaps":["Single lab, not independently confirmed","Direct vs. indirect bridging of ERβ to PIAS1 unclear","Generality beyond ERβ not tested"]},{"year":2018,"claim":"Linked RSRC1 loss to autosomal recessive intellectual disability and connected the disease mechanism to aberrant splicing and transcription, establishing physiological importance in neurodevelopment.","evidence":"Homozygosity mapping, exome sequencing, NMD confirmation in patient fibroblasts, shRNA silencing/overexpression in SH-SY5Y cells with transcriptome profiling, and patient iPSC-derived neural progenitor validation","pmids":["29522154"],"confidence":"High","gaps":["Causal splicing events driving the neuronal phenotype not pinpointed","Mechanism connecting RSRC1 loss to IGFBP3 downregulation not resolved","No rescue in patient neurons"]},{"year":2019,"claim":"Implicated RSRC1 as a tumor suppressor in gastric cancer by tying its loss to increased proliferation/migration and reduced PTEN, addressing whether RSRC1 has growth-regulatory function.","evidence":"siRNA knockdown in gastric cancer cells with proliferation, EdU, and Transwell assays plus PTEN Western blot and RT-qPCR","pmids":["31257492"],"confidence":"Medium","gaps":["No rescue or epistasis experiment","Whether PTEN regulation is via splicing or transcription not determined","In vivo tumor relevance untested"]},{"year":2025,"claim":"Identified RSRC1 as an evolutionarily conserved modulator of aging by showing ortholog knockdown extends lifespan, raising the possibility of a conserved organismal function.","evidence":"Post-developmental RNAi of spch-2 in C. elegans with replicated lifespan assays","pmids":["41078088"],"confidence":"Medium","gaps":["Relevance to mammalian RSRC1 inferred only by orthology","Molecular pathway linking RSRC1 to longevity unknown","Whether splicing or transcription drives the lifespan effect untested"]},{"year":null,"claim":"How RSRC1's splicing activity, SUMO-dependent transcriptional coregulation, and target gene control (PTEN, IGFBP3, ERβ) mechanistically integrate into a single biochemical program remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying mechanism connecting splicing and transcription roles","No structural model of RSRC1","Direct endogenous RNA and protein targets not comprehensively mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,3]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2]}],"complexes":[],"partners":["U2AF1","U2AF2","HCC1","ESR2","PIAS1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96IZ7","full_name":"Serine/Arginine-related protein 53","aliases":["Arginine/serine-rich coiled-coil protein 1"],"length_aa":334,"mass_kda":38.7,"function":"Has a role in alternative splicing and transcription regulation (PubMed:29522154). Involved in both constitutive and alternative pre-mRNA splicing. May have a role in the recognition of the 3' splice site during the second step of splicing","subcellular_location":"Nucleus; Nucleus speckle; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q96IZ7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RSRC1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"COMMD2","stoichiometry":10.0},{"gene":"DKC1","stoichiometry":10.0},{"gene":"RANBP2","stoichiometry":10.0},{"gene":"RSL1D1","stoichiometry":10.0},{"gene":"COMMD6","stoichiometry":4.0},{"gene":"GNL3","stoichiometry":4.0},{"gene":"NOP10","stoichiometry":4.0},{"gene":"AAMP","stoichiometry":0.2},{"gene":"CD2BP2","stoichiometry":0.2},{"gene":"CDKN2A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RSRC1","total_profiled":1310},"omim":[{"mim_id":"618402","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 70; MRT70","url":"https://www.omim.org/entry/618402"},{"mim_id":"613352","title":"ARGININE/SERINE-RICH COILED-COIL PROTEIN 1; RSRC1","url":"https://www.omim.org/entry/613352"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RSRC1"},"hgnc":{"alias_symbol":["MGC12197","BM-011","SRrp53","SFRS21"],"prev_symbol":[]},"alphafold":{"accession":"Q96IZ7","domains":[{"cath_id":"1.20.5","chopping":"168-235","consensus_level":"high","plddt":78.3906,"start":168,"end":235}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96IZ7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96IZ7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96IZ7-F1-predicted_aligned_error_v6.png","plddt_mean":58.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RSRC1","jax_strain_url":"https://www.jax.org/strain/search?query=RSRC1"},"sequence":{"accession":"Q96IZ7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96IZ7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96IZ7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96IZ7"}},"corpus_meta":[{"pmid":"26881967","id":"PMC_26881967","title":"Therapeutic potential of targeting microRNA-10b in established intracranial glioblastoma: first steps toward the clinic.","date":"2016","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26881967","citation_count":116,"is_preprint":false},{"pmid":"20600988","id":"PMC_20600988","title":"Identifying gene regulatory networks in schizophrenia.","date":"2010","source":"NeuroImage","url":"https://pubmed.ncbi.nlm.nih.gov/20600988","citation_count":100,"is_preprint":false},{"pmid":"19065146","id":"PMC_19065146","title":"Gene discovery through imaging genetics: identification of two novel genes associated with schizophrenia.","date":"2008","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/19065146","citation_count":81,"is_preprint":false},{"pmid":"28545128","id":"PMC_28545128","title":"Common variants upstream of MLF1 at 3q25 and within CPZ at 4p16 associated with neuroblastoma.","date":"2017","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28545128","citation_count":71,"is_preprint":false},{"pmid":"15798186","id":"PMC_15798186","title":"A novel SR-related protein is required for the second step of Pre-mRNA splicing.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15798186","citation_count":54,"is_preprint":false},{"pmid":"30532555","id":"PMC_30532555","title":"Identification of tumor-educated platelet biomarkers of non-small-cell lung cancer.","date":"2018","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30532555","citation_count":50,"is_preprint":false},{"pmid":"24214394","id":"PMC_24214394","title":"Discovery of recurrent structural variants in nasopharyngeal carcinoma.","date":"2013","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/24214394","citation_count":36,"is_preprint":false},{"pmid":"29728651","id":"PMC_29728651","title":"Common variants on 6q16.2, 12q24.31 and 16p13.3 are associated with major depressive disorder.","date":"2018","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29728651","citation_count":32,"is_preprint":false},{"pmid":"29522154","id":"PMC_29522154","title":"RSRC1 mutation affects intellect and behaviour through aberrant splicing and transcription, downregulating IGFBP3.","date":"2018","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/29522154","citation_count":22,"is_preprint":false},{"pmid":"37095490","id":"PMC_37095490","title":"A novel protein encoded by circRsrc1 regulates mitochondrial ribosome assembly and translation during spermatogenesis.","date":"2023","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/37095490","citation_count":22,"is_preprint":false},{"pmid":"34638998","id":"PMC_34638998","title":"BCL-2 Inhibitor ABT-737 Effectively Targets Leukemia-Initiating Cells with Differential Regulation of Relevant Genes Leading to Extended Survival in a NRAS/BCL-2 Mouse Model of High Risk-Myelodysplastic Syndrome.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34638998","citation_count":15,"is_preprint":false},{"pmid":"25937118","id":"PMC_25937118","title":"RSRC1 SUMOylation enhances SUMOylation and inhibits transcriptional activity of estrogen receptor β.","date":"2015","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/25937118","citation_count":12,"is_preprint":false},{"pmid":"40078563","id":"PMC_40078563","title":"Improving neuroblastoma risk prediction through a polygenic risk score derived from genome-wide association study-identified loci.","date":"2025","source":"Chinese journal of cancer research = Chung-kuo yen cheng yen chiu","url":"https://pubmed.ncbi.nlm.nih.gov/40078563","citation_count":8,"is_preprint":false},{"pmid":"31257492","id":"PMC_31257492","title":"RSRC1 suppresses gastric cancer cell proliferation and migration by regulating PTEN expression.","date":"2019","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/31257492","citation_count":7,"is_preprint":false},{"pmid":"29653227","id":"PMC_29653227","title":"RSRC1 and CPZ gene polymorphisms with neuroblastoma susceptibility in Chinese children.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/29653227","citation_count":5,"is_preprint":false},{"pmid":"38806690","id":"PMC_38806690","title":"Mutational landscape of risk variants in comorbid depression and obesity: a next-generation sequencing approach.","date":"2024","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/38806690","citation_count":4,"is_preprint":false},{"pmid":"37572583","id":"PMC_37572583","title":"Identification of a novel RSRC1-ALK (R6: A20) fusion using next-generation sequencing technique.","date":"2023","source":"Cancer 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SRrp53 from HeLa nuclear extracts blocks the second step of splicing, and recombinant SRrp53 restores splicing activity. SRrp53 interacts with the mouse ortholog of yeast U1 snRNP-specific protein Luc7p, the U2AF65-related factor HCC1, members of the SR protein family, and U2AF35 (shown by yeast two-hybrid and in cell extracts). SRrp53 also regulates alternative splicing in a concentration-dependent manner. The protein localizes to nuclear speckles.\",\n      \"method\": \"Immunodepletion/reconstitution of splicing in HeLa nuclear extracts; yeast two-hybrid; co-immunoprecipitation from cell extracts; gene trap screen for nuclear speckle localization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of splicing activity with immunodepletion and recombinant protein rescue, supported by two orthogonal protein-interaction methods (yeast two-hybrid + co-IP), single lab\",\n      \"pmids\": [\"15798186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RSRC1 interacts with estrogen receptor β (ERβ) and promotes PIAS1-mediated SUMOylation of ERβ; SUMOylation of RSRC1 itself is required for this regulatory activity. Through this mechanism RSRC1 represses ERβ transcriptional activity.\",\n      \"method\": \"Co-immunoprecipitation; SUMOylation assays; transcriptional reporter assays; mutagenesis of SUMO sites on RSRC1\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional transcriptional assay and mutagenesis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25937118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss-of-function RSRC1 mutation (causing nonsense-mediated mRNA decay) in patients causes autosomal recessive intellectual disability, aberrant behaviour, hypotonia, and mild facial dysmorphism. shRNA-mediated silencing in SH-SY5Y cells demonstrates RSRC1 has a role in alternative splicing and transcription regulation. RSRC1 loss leads to downregulation of IGFBP3 (9.6-fold) in patient-derived iPSC-differentiated neural progenitor cells. Protein-protein interaction network modelling identified intermediate interactions mediating gene-specific differential expression.\",\n      \"method\": \"Homozygosity mapping; whole exome sequencing; RT-PCR (NMD confirmation in patient fibroblasts); shRNA lentiviral silencing and overexpression in SH-SY5Y cells; transcriptome profiling; iPSC differentiation to neural progenitor cells\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function in patient cells confirmed by NMD, functional rescue/silencing experiments in neuronal cell line with transcriptome readout, and patient iPSC-derived NPC validation; multiple orthogonal methods across independent cell systems\",\n      \"pmids\": [\"29522154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RSRC1 knockdown in gastric cancer cells promotes proliferation and migration, and decreases PTEN protein and mRNA expression, indicating RSRC1 suppresses gastric cancer cell growth at least partly by maintaining PTEN expression.\",\n      \"method\": \"siRNA knockdown; Cell Counting Kit-8 proliferation assay; EdU incorporation assay; Transwell migration assay; Western blot and RT-qPCR for PTEN\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined cellular phenotype and molecular readout (PTEN), single lab, multiple functional assays but no rescue or epistasis experiment\",\n      \"pmids\": [\"31257492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNAi knockdown of spch-2, the C. elegans ortholog of RSRC1, produces significant and reproducible lifespan extension in C. elegans, identifying RSRC1 as an evolutionarily conserved driver of aging.\",\n      \"method\": \"Post-developmental RNA interference in C. elegans; lifespan assay (two independent trials, ~100 animals per genotype per trial)\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with replicated quantitative lifespan phenotype in a model organism ortholog; functional relevance to canonical mammalian RSRC1 is inferred by orthology\",\n      \"pmids\": [\"41078088\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RSRC1 (SRrp53) is an SR-related nuclear protein that localizes to nuclear speckles, directly participates in both constitutive and alternative pre-mRNA splicing (required for the second catalytic step), interacts with spliceosomal components (Luc7p ortholog, HCC1, SR proteins, U2AF35/U2AF65), regulates transcription (including PTEN and IGFBP3 expression), and modulates ERβ transcriptional activity by promoting PIAS1-dependent ERβ SUMOylation in a manner dependent on RSRC1's own SUMOylation; loss of RSRC1 function in humans causes intellectual disability through aberrant splicing and transcription, and its C. elegans ortholog knockdown extends lifespan.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RSRC1 (SRrp53) is an SR-related nuclear protein that couples pre-mRNA splicing to transcriptional regulation and is essential for normal neurodevelopment [#0, #2]. In nuclear speckles it acts as a splicing factor specifically required for the second catalytic step of pre-mRNA splicing, functioning through interactions with the Luc7p ortholog, the U2AF65-related factor HCC1, SR-family proteins, and U2AF35, and it modulates alternative splice-site choice in a concentration-dependent manner [#0]. Beyond constitutive splicing, RSRC1 regulates gene expression: it represses estrogen receptor \\u03b2 transcriptional activity by promoting PIAS1-dependent SUMOylation of ER\\u03b2 in a manner that itself depends on RSRC1 SUMOylation [#1], and it sustains expression of targets including PTEN and IGFBP3 [#2, #3]. Loss-of-function RSRC1 mutations that trigger nonsense-mediated decay cause autosomal recessive intellectual disability with hypotonia and mild dysmorphism, linked to aberrant splicing and transcription in patient-derived neural progenitors [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that RSRC1/SRrp53 is a functional splicing factor by defining its specific requirement in the second catalytic step and its spliceosomal interaction network, answering whether the protein had a direct biochemical role in splicing.\",\n      \"evidence\": \"Immunodepletion/reconstitution of splicing in HeLa nuclear extracts with recombinant rescue, plus yeast two-hybrid and co-IP mapping of interactions with Luc7p ortholog, HCC1, SR proteins, and U2AF35\",\n      \"pmids\": [\"15798186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of second-step participation not resolved\", \"No genome-wide map of endogenous splicing targets\", \"Concentration-dependence of alternative splicing not linked to specific transcripts\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended RSRC1 function from splicing to transcriptional control by showing it represses ER\\u03b2 via SUMO-dependent regulation, revealing a SUMOylation-gated coregulator activity.\",\n      \"evidence\": \"Co-IP, SUMOylation assays, transcriptional reporters, and mutagenesis of RSRC1 SUMO sites\",\n      \"pmids\": [\"25937118\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, not independently confirmed\", \"Direct vs. indirect bridging of ER\\u03b2 to PIAS1 unclear\", \"Generality beyond ER\\u03b2 not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked RSRC1 loss to autosomal recessive intellectual disability and connected the disease mechanism to aberrant splicing and transcription, establishing physiological importance in neurodevelopment.\",\n      \"evidence\": \"Homozygosity mapping, exome sequencing, NMD confirmation in patient fibroblasts, shRNA silencing/overexpression in SH-SY5Y cells with transcriptome profiling, and patient iPSC-derived neural progenitor validation\",\n      \"pmids\": [\"29522154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal splicing events driving the neuronal phenotype not pinpointed\", \"Mechanism connecting RSRC1 loss to IGFBP3 downregulation not resolved\", \"No rescue in patient neurons\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Implicated RSRC1 as a tumor suppressor in gastric cancer by tying its loss to increased proliferation/migration and reduced PTEN, addressing whether RSRC1 has growth-regulatory function.\",\n      \"evidence\": \"siRNA knockdown in gastric cancer cells with proliferation, EdU, and Transwell assays plus PTEN Western blot and RT-qPCR\",\n      \"pmids\": [\"31257492\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No rescue or epistasis experiment\", \"Whether PTEN regulation is via splicing or transcription not determined\", \"In vivo tumor relevance untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified RSRC1 as an evolutionarily conserved modulator of aging by showing ortholog knockdown extends lifespan, raising the possibility of a conserved organismal function.\",\n      \"evidence\": \"Post-developmental RNAi of spch-2 in C. elegans with replicated lifespan assays\",\n      \"pmids\": [\"41078088\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relevance to mammalian RSRC1 inferred only by orthology\", \"Molecular pathway linking RSRC1 to longevity unknown\", \"Whether splicing or transcription drives the lifespan effect untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RSRC1's splicing activity, SUMO-dependent transcriptional coregulation, and target gene control (PTEN, IGFBP3, ER\\u03b2) mechanistically integrate into a single biochemical program remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying mechanism connecting splicing and transcription roles\", \"No structural model of RSRC1\", \"Direct endogenous RNA and protein targets not comprehensively mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"U2AF1\", \"U2AF2\", \"HCC1\", \"ESR2\", \"PIAS1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}