{"gene":"CIRSR","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2020,"finding":"Cryo-EM structure of the human spliceosomal C complex at 3.4 Å core resolution revealed that the metazoan-specific protein CIR1 is spatially organized within the C complex, where it stabilizes functionally important protein domains and RNA structures that are rearranged/repositioned during the Bact-to-C transition.","method":"Cryo-EM structure determination at 3.4 Å (core) with protein crosslinking/MS for molecular architecture assignment","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure with crosslinking mass spectrometry validation; single rigorous study with multiple orthogonal structural methods","pmids":["33007253"],"is_preprint":false},{"year":2021,"finding":"RYBP directly interacts with CIR1, and this interaction facilitates binding of RBPJ to the Notch intracellular domain (NICD), thereby activating Notch signaling. Upon Rybp loss, CIR1 competes with RBPJ to bind NICD, inhibiting Notch signaling and promoting neuronal differentiation of embryonic neural progenitor cells.","method":"Co-immunoprecipitation (direct interaction of RYBP and CIR1); loss-of-function (Rybp depletion) with Notch signaling readouts; rescue experiment with Hes5 overexpression","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP for interaction, KD with defined signaling phenotype and rescue, single lab with two orthogonal methods","pmids":["34798064"],"is_preprint":false},{"year":2010,"finding":"In C. elegans, MOG-3 binds to the CSL co-repressor CIR-1 (ortholog of mammalian CIR1) and to MEP-1 in the nucleus, and this complex regulates germ cell development including meiosis and sex determination; the mammalian CIR1 homolog is noted to counter Notch signaling.","method":"Yeast two-hybrid and co-immunoprecipitation demonstrating MOG-3 interaction with CIR-1; genetic epistasis (mog-3 mutant phenotypes downstream of GLP-1/Notch)","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays and genetic epistasis in C. elegans ortholog, single lab","pmids":["20478293"],"is_preprint":false},{"year":1998,"finding":"CIR1 (identical to CROC1/UEV-1) transcript is upregulated 5–6-fold in immortalized human cells immediately following proliferative crisis compared to pre-immortal counterparts, and is also elevated in a variety of immortal tumor-derived human cell lines relative to normal tissue.","method":"mRNA differential display comparing genetically matched pre-immortal and immortal human cell clones; Northern blot validation","journal":"Oncogene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — expression-level finding (differential display + Northern blot), no mechanistic functional assay linking CIR1 activity to immortalization mechanism","pmids":["9771976"],"is_preprint":false},{"year":2014,"finding":"RNAi inhibition of cir-1 (C. elegans ortholog of CIR1) accelerated cell division timing in specific cells of the AB lineage during early embryogenesis, a phenotype also produced by inhibition of RNA polymerase II, suggesting CIR1 function is linked to transcriptional regulation that normally delays cell cycle progression.","method":"Semi-automated nuclear tracking of all nuclei during C. elegans early development following RNAi knockdown; epistasis with RNA polymerase II inhibition","journal":"Developmental biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single RNAi screen in C. elegans ortholog, no direct biochemical mechanism established for CIR1 itself","pmids":["25446273"],"is_preprint":false}],"current_model":"Human CIRSR (CIR1) is a metazoan-specific spliceosomal protein that localizes to the C complex where it stabilizes protein domains and RNA structures during the Bact-to-C transition, and also functions as a Notch pathway corepressor whose interaction with RYBP facilitates RBPJ binding to the Notch intracellular domain to activate Notch target gene transcription."},"narrative":{"mechanistic_narrative":"CIRSR (CIR1) is a metazoan-specific spliceosomal protein and CSL/Notch corepressor that operates at the interface of pre-mRNA splicing and transcriptional regulation of the Notch pathway [PMID:33007253, PMID:34798064]. Within the human spliceosomal C complex, CIR1 is spatially integrated into the catalytic machinery where it stabilizes protein domains and RNA structures that are rearranged during the Bact-to-C transition [PMID:33007253]. In Notch signaling, CIR1 is bound directly by RYBP, an interaction that promotes RBPJ association with the Notch intracellular domain (NICD) to activate Notch target genes; in the absence of RYBP, CIR1 instead competes with RBPJ for NICD binding, repressing Notch signaling and driving neuronal differentiation of embryonic neural progenitors [PMID:34798064]. This corepressor role is conserved: the C. elegans ortholog CIR-1 acts as a CSL corepressor that, together with MOG-3 and MEP-1, regulates germline meiosis and sex determination [PMID:20478293].","teleology":[{"year":1998,"claim":"Before any function was known, it was unclear whether CIR1 expression tracked with cellular states, and the first link came from associating its transcript level with cellular immortalization.","evidence":"mRNA differential display and Northern blot comparing pre-immortal vs. immortal human cell clones and tumor-derived lines","pmids":["9771976"],"confidence":"Low","gaps":["Expression correlation only; no functional assay linking CIR1 activity to immortalization mechanism","Does not define a molecular function for the protein"]},{"year":2010,"claim":"Whether CIR1's corepressor role was conserved and what partners it used in vivo was unknown; work in C. elegans placed the ortholog CIR-1 in a nuclear complex controlling germ cell fate.","evidence":"Yeast two-hybrid and Co-IP showing MOG-3 binds CIR-1 and MEP-1, with genetic epistasis downstream of GLP-1/Notch in C. elegans","pmids":["20478293"],"confidence":"Medium","gaps":["Mapped in the worm ortholog, not human CIR1","Biochemical mechanism of CSL corepression not resolved","Direct link between complex composition and Notch output not established at molecular level"]},{"year":2014,"claim":"It was unknown whether CIR1 influences cell cycle progression; RNAi of the worm ortholog tied its loss to accelerated division, phenocopying RNA Pol II inhibition and implicating transcriptional regulation.","evidence":"Semi-automated nuclear tracking after cir-1 RNAi in C. elegans embryos, with epistasis to RNA polymerase II inhibition","pmids":["25446273"],"confidence":"Low","gaps":["Single RNAi phenotype in ortholog; no direct biochemical mechanism for CIR1","Causal connection between transcriptional role and division timing not defined"]},{"year":2020,"claim":"The molecular context of CIR1 in the spliceosome was unresolved until a high-resolution structure placed it within the catalytic C complex as a stabilizing component.","evidence":"Cryo-EM of the human spliceosomal C complex at 3.4 Å core resolution with crosslinking/MS architecture assignment","pmids":["33007253"],"confidence":"High","gaps":["Structural placement does not establish a catalytic or regulatory function for CIR1 in splicing","Whether CIR1's spliceosomal and Notch corepressor roles are mechanistically linked is unaddressed"]},{"year":2021,"claim":"How CIR1 switches between activating and repressing Notch was unknown; RYBP was identified as a direct partner that toggles CIR1 between promoting RBPJ–NICD binding and competing with RBPJ.","evidence":"Reciprocal Co-IP for RYBP–CIR1 interaction, Rybp loss-of-function with Notch readouts, and Hes5 rescue in embryonic neural progenitors","pmids":["34798064"],"confidence":"Medium","gaps":["Structural basis of competition for NICD binding not determined","Single lab using Co-IP and knockdown; reciprocal validation in other cell types absent","Connection to CIR1's spliceosomal function not explored"]},{"year":null,"claim":"It remains unknown whether CIR1's role as a spliceosomal C-complex component and its role as a Notch/CSL corepressor are functionally coupled or represent independent activities.","evidence":"","pmids":[],"confidence":"Low","gaps":["No study integrates the splicing and transcriptional corepressor functions","No human structural or biochemical mechanism for CSL corepression","No identified splicing substrates dependent on CIR1"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1]}],"complexes":["spliceosomal C complex"],"partners":["RYBP","RBPJ","MEP-1","MOG-3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86X95","full_name":"Corepressor of RBPJ and splicing regulator","aliases":["CBF1-interacting corepressor","Corepressor interacting with RBPJ 1","Recepin"],"length_aa":450,"mass_kda":52.3,"function":"May modulate splice site selection during alternative splicing of pre-mRNAs (By similarity). Regulates transcription and acts as corepressor for RBPJ. Recruits RBPJ to the Sin3-histone deacetylase complex (HDAC). Required for RBPJ-mediated repression of transcription","subcellular_location":"Nucleus speckle; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q86X95/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CIRSR","classification":"Not Classified","n_dependent_lines":385,"n_total_lines":1208,"dependency_fraction":0.31870860927152317},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CIRSR","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"CIR1","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CIR1"},"hgnc":{"alias_symbol":["CIR"],"prev_symbol":["CIR1"]},"alphafold":{"accession":"Q86X95","domains":[{"cath_id":"-","chopping":"122-159","consensus_level":"medium","plddt":72.0071,"start":122,"end":159},{"cath_id":"1.20.5","chopping":"15-74","consensus_level":"medium","plddt":89.3135,"start":15,"end":74}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86X95","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86X95-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86X95-F1-predicted_aligned_error_v6.png","plddt_mean":59.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CIRSR","jax_strain_url":"https://www.jax.org/strain/search?query=CIRSR"},"sequence":{"accession":"Q86X95","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86X95.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86X95/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86X95"}},"corpus_meta":[{"pmid":"17121456","id":"PMC_17121456","title":"Iron 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Homeostasis and Virulence in Cryptococcus neoformans.","date":"2018","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/30514787","citation_count":50,"is_preprint":false},{"pmid":"9482666","id":"PMC_9482666","title":"Identification and characterization of a novel corepressor interaction region in RVR and Rev-erbA alpha.","date":"1998","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/9482666","citation_count":39,"is_preprint":false},{"pmid":"33007253","id":"PMC_33007253","title":"Structural Insights into the Roles of Metazoan-Specific Splicing Factors in the Human Step 1 Spliceosome.","date":"2020","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/33007253","citation_count":38,"is_preprint":false},{"pmid":"9771976","id":"PMC_9771976","title":"Up-regulation of CIR1/CROC1 expression upon cell immortalization and in tumor-derived human cell 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bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/12897020","citation_count":17,"is_preprint":false},{"pmid":"33760942","id":"PMC_33760942","title":"Coordinated regulation of iron metabolism in Cryptococcus neoformans by GATA and CCAAT transcription factors: connections with virulence.","date":"2021","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33760942","citation_count":16,"is_preprint":false},{"pmid":"20478293","id":"PMC_20478293","title":"The C. elegans sex determination protein MOG-3 functions in meiosis and binds to the CSL co-repressor CIR-1.","date":"2010","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/20478293","citation_count":15,"is_preprint":false},{"pmid":"21963719","id":"PMC_21963719","title":"Iron influences the abundance of the iron regulatory protein Cir1 in the fungal pathogen Cryptococcus neoformans.","date":"2011","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/21963719","citation_count":15,"is_preprint":false},{"pmid":"34542604","id":"PMC_34542604","title":"The monothiol glutaredoxin Grx4 influences thermotolerance, cell wall integrity, and Mpk1 signaling in Cryptococcus neoformans.","date":"2021","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/34542604","citation_count":15,"is_preprint":false},{"pmid":"38004632","id":"PMC_38004632","title":"Effects of Maize-Crop Rotation on Soil Physicochemical Properties, Enzyme Activities, Microbial Biomass and Microbial Community Structure in Southwest China.","date":"2023","source":"Microorganisms","url":"https://pubmed.ncbi.nlm.nih.gov/38004632","citation_count":13,"is_preprint":false},{"pmid":"34798064","id":"PMC_34798064","title":"RYBP modulates embryonic neurogenesis involving the Notch signaling pathway in a PRC1-independent pattern.","date":"2021","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34798064","citation_count":13,"is_preprint":false},{"pmid":"8139924","id":"PMC_8139924","title":"An operator associated with autoregulation of the repressor gene in actinophage phiC31 is found in highly conserved copies in intergenic regions in the phage genome.","date":"1994","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/8139924","citation_count":12,"is_preprint":false},{"pmid":"36656038","id":"PMC_36656038","title":"Factors Influencing the Nitrogen-Source Dependent Flucytosine Resistance in Cryptococcus Species.","date":"2023","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/36656038","citation_count":7,"is_preprint":false},{"pmid":"27587543","id":"PMC_27587543","title":"Polymorphisms in cancer-related pathway genes and lung cancer.","date":"2016","source":"The European respiratory 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Part B, Resources","url":"https://pubmed.ncbi.nlm.nih.gov/34345704","citation_count":5,"is_preprint":false},{"pmid":"31706700","id":"PMC_31706700","title":"Impact of iron chelators on growth and expression of iron-related genes of Cryptococcus species.","date":"2019","source":"Journal de mycologie medicale","url":"https://pubmed.ncbi.nlm.nih.gov/31706700","citation_count":4,"is_preprint":false},{"pmid":"38405941","id":"PMC_38405941","title":"The interplay between electron transport chain function and iron regulatory factors influences melanin formation in Cryptococcus neoformans.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38405941","citation_count":1,"is_preprint":false},{"pmid":"19134256","id":"PMC_19134256","title":"[Mechanism of conditioned immune response in curing bronchial asthma in mice].","date":"2008","source":"Zhonghua er ke za zhi = Chinese journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/19134256","citation_count":1,"is_preprint":false},{"pmid":"40787456","id":"PMC_40787456","title":"The kinase Bud32 regulates iron homeostasis in fungal pathogen Cryptococcus neoformans.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40787456","citation_count":0,"is_preprint":false},{"pmid":"33326159","id":"PMC_33326159","title":"Methods to Validate Binding and Kinetics of \"Proximity-Inducing\" Covalent Immune-Recruiting Molecules.","date":"2020","source":"Current protocols in chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/33326159","citation_count":0,"is_preprint":false},{"pmid":"41843179","id":"PMC_41843179","title":"Integrative transcriptomic analysis reveals alternative splicing programs in sepsis-induced myocardial injury across dual mouse models.","date":"2026","source":"Inflammation research : official journal of the European Histamine Research Society ... [et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/41843179","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20476,"output_tokens":1733,"usd":0.043712,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7920,"output_tokens":2142,"usd":0.046575,"stage2_stop_reason":"end_turn"},"total_usd":0.090287,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify what gene \"CIRSR\" with alias \"CIR1\" refers to. The corpus contains papers about multiple different proteins/entities named CIR1:\n\n1. **Cryptococcus neoformans Cir1** - a GATA-type iron-regulatory transcription factor (fungal pathogen)\n2. **Human/mammalian CIRSR/CIR1** - \"corepressor interacting with RBPJ 1\" - involved in Notch signaling, spliceosome\n3. **C. elegans cir-1** - CSL co-repressor\n4. Other collisions (bacterial, plant, agricultural)\n\nGiven HGNC gene symbol CIRSR with alias CIR1 = \"corepressor interacting with RBPJ 1\" (human gene), I need to focus on the mammalian/human CIR1 papers. The Cryptococcus Cir1 is a fungal GATA factor — a completely different protein. The human CIRSR/CIR1 is the spliceosomal/Notch corepressor protein.\n\nRelevant papers for human CIRSR (CIR1):\n- PMID:33007253 - cryo-EM structure of human spliceosome C complex, CIR1 location\n- PMID:34798064 - RYBP interacts with CIR1 in Notch signaling\n- PMID:20478293 - C. elegans MOG-3 binds CIR-1 (mammalian homolog counters Notch signaling)\n- PMID:9771976 - CIR1/CROC1 upregulation in immortalization\n- PMID:25446273 - C. elegans cir-1 RNAi accelerates cell division\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM structure of the human spliceosomal C complex at 3.4 Å core resolution revealed that the metazoan-specific protein CIR1 is spatially organized within the C complex, where it stabilizes functionally important protein domains and RNA structures that are rearranged/repositioned during the Bact-to-C transition.\",\n      \"method\": \"Cryo-EM structure determination at 3.4 Å (core) with protein crosslinking/MS for molecular architecture assignment\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure with crosslinking mass spectrometry validation; single rigorous study with multiple orthogonal structural methods\",\n      \"pmids\": [\"33007253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RYBP directly interacts with CIR1, and this interaction facilitates binding of RBPJ to the Notch intracellular domain (NICD), thereby activating Notch signaling. Upon Rybp loss, CIR1 competes with RBPJ to bind NICD, inhibiting Notch signaling and promoting neuronal differentiation of embryonic neural progenitor cells.\",\n      \"method\": \"Co-immunoprecipitation (direct interaction of RYBP and CIR1); loss-of-function (Rybp depletion) with Notch signaling readouts; rescue experiment with Hes5 overexpression\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP for interaction, KD with defined signaling phenotype and rescue, single lab with two orthogonal methods\",\n      \"pmids\": [\"34798064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In C. elegans, MOG-3 binds to the CSL co-repressor CIR-1 (ortholog of mammalian CIR1) and to MEP-1 in the nucleus, and this complex regulates germ cell development including meiosis and sex determination; the mammalian CIR1 homolog is noted to counter Notch signaling.\",\n      \"method\": \"Yeast two-hybrid and co-immunoprecipitation demonstrating MOG-3 interaction with CIR-1; genetic epistasis (mog-3 mutant phenotypes downstream of GLP-1/Notch)\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays and genetic epistasis in C. elegans ortholog, single lab\",\n      \"pmids\": [\"20478293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CIR1 (identical to CROC1/UEV-1) transcript is upregulated 5–6-fold in immortalized human cells immediately following proliferative crisis compared to pre-immortal counterparts, and is also elevated in a variety of immortal tumor-derived human cell lines relative to normal tissue.\",\n      \"method\": \"mRNA differential display comparing genetically matched pre-immortal and immortal human cell clones; Northern blot validation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — expression-level finding (differential display + Northern blot), no mechanistic functional assay linking CIR1 activity to immortalization mechanism\",\n      \"pmids\": [\"9771976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RNAi inhibition of cir-1 (C. elegans ortholog of CIR1) accelerated cell division timing in specific cells of the AB lineage during early embryogenesis, a phenotype also produced by inhibition of RNA polymerase II, suggesting CIR1 function is linked to transcriptional regulation that normally delays cell cycle progression.\",\n      \"method\": \"Semi-automated nuclear tracking of all nuclei during C. elegans early development following RNAi knockdown; epistasis with RNA polymerase II inhibition\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single RNAi screen in C. elegans ortholog, no direct biochemical mechanism established for CIR1 itself\",\n      \"pmids\": [\"25446273\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human CIRSR (CIR1) is a metazoan-specific spliceosomal protein that localizes to the C complex where it stabilizes protein domains and RNA structures during the Bact-to-C transition, and also functions as a Notch pathway corepressor whose interaction with RYBP facilitates RBPJ binding to the Notch intracellular domain to activate Notch target gene transcription.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CIRSR (CIR1) is a metazoan-specific spliceosomal protein and CSL/Notch corepressor that operates at the interface of pre-mRNA splicing and transcriptional regulation of the Notch pathway [#0, #1]. Within the human spliceosomal C complex, CIR1 is spatially integrated into the catalytic machinery where it stabilizes protein domains and RNA structures that are rearranged during the Bact-to-C transition [#0]. In Notch signaling, CIR1 is bound directly by RYBP, an interaction that promotes RBPJ association with the Notch intracellular domain (NICD) to activate Notch target genes; in the absence of RYBP, CIR1 instead competes with RBPJ for NICD binding, repressing Notch signaling and driving neuronal differentiation of embryonic neural progenitors [#1]. This corepressor role is conserved: the C. elegans ortholog CIR-1 acts as a CSL corepressor that, together with MOG-3 and MEP-1, regulates germline meiosis and sex determination [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Before any function was known, it was unclear whether CIR1 expression tracked with cellular states, and the first link came from associating its transcript level with cellular immortalization.\",\n      \"evidence\": \"mRNA differential display and Northern blot comparing pre-immortal vs. immortal human cell clones and tumor-derived lines\",\n      \"pmids\": [\"9771976\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Expression correlation only; no functional assay linking CIR1 activity to immortalization mechanism\",\n        \"Does not define a molecular function for the protein\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Whether CIR1's corepressor role was conserved and what partners it used in vivo was unknown; work in C. elegans placed the ortholog CIR-1 in a nuclear complex controlling germ cell fate.\",\n      \"evidence\": \"Yeast two-hybrid and Co-IP showing MOG-3 binds CIR-1 and MEP-1, with genetic epistasis downstream of GLP-1/Notch in C. elegans\",\n      \"pmids\": [\"20478293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mapped in the worm ortholog, not human CIR1\",\n        \"Biochemical mechanism of CSL corepression not resolved\",\n        \"Direct link between complex composition and Notch output not established at molecular level\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"It was unknown whether CIR1 influences cell cycle progression; RNAi of the worm ortholog tied its loss to accelerated division, phenocopying RNA Pol II inhibition and implicating transcriptional regulation.\",\n      \"evidence\": \"Semi-automated nuclear tracking after cir-1 RNAi in C. elegans embryos, with epistasis to RNA polymerase II inhibition\",\n      \"pmids\": [\"25446273\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single RNAi phenotype in ortholog; no direct biochemical mechanism for CIR1\",\n        \"Causal connection between transcriptional role and division timing not defined\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The molecular context of CIR1 in the spliceosome was unresolved until a high-resolution structure placed it within the catalytic C complex as a stabilizing component.\",\n      \"evidence\": \"Cryo-EM of the human spliceosomal C complex at 3.4 Å core resolution with crosslinking/MS architecture assignment\",\n      \"pmids\": [\"33007253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural placement does not establish a catalytic or regulatory function for CIR1 in splicing\",\n        \"Whether CIR1's spliceosomal and Notch corepressor roles are mechanistically linked is unaddressed\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"How CIR1 switches between activating and repressing Notch was unknown; RYBP was identified as a direct partner that toggles CIR1 between promoting RBPJ–NICD binding and competing with RBPJ.\",\n      \"evidence\": \"Reciprocal Co-IP for RYBP–CIR1 interaction, Rybp loss-of-function with Notch readouts, and Hes5 rescue in embryonic neural progenitors\",\n      \"pmids\": [\"34798064\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis of competition for NICD binding not determined\",\n        \"Single lab using Co-IP and knockdown; reciprocal validation in other cell types absent\",\n        \"Connection to CIR1's spliceosomal function not explored\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether CIR1's role as a spliceosomal C-complex component and its role as a Notch/CSL corepressor are functionally coupled or represent independent activities.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No study integrates the splicing and transcriptional corepressor functions\",\n        \"No human structural or biochemical mechanism for CSL corepression\",\n        \"No identified splicing substrates dependent on CIR1\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"spliceosomal C complex\"],\n    \"partners\": [\"RYBP\", \"RBPJ\", \"MEP-1\", \"MOG-3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}