{"gene":"ANAPC13","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2004,"finding":"Swm1/Apc13 (ANAPC13) is an evolutionarily conserved subunit of the APC/C that promotes the stable association of the essential TPR subunits Cdc16 and Cdc27 with the complex; deletion of SWM1 reduces APC/C ubiquitin ligase activity in vitro and delays APC/C-dependent cell cycle events in vivo. Human and fission yeast homologues associate with APC/C subunits and complement the yeast swm1Δ phenotype.","method":"Mass spectrometry, co-purification, in vitro ubiquitin ligase assay, complementation assay, cell cycle analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro ubiquitin ligase reconstitution combined with genetic complementation across species and subunit-association assays; independently replicated across papers 4 and 5","pmids":["15060174"],"is_preprint":false},{"year":2003,"finding":"Swm1 (ANAPC13) was identified as a constitutive core subunit of the budding yeast APC/C, present throughout G1, S, and M phases and in meiotic cells. Swm1 interacts with Cdc23 (APC8) and Apc5 in an in vitro transcription/translation system. Deletion of SWM1 causes slow growth and G2/M accumulation consistent with an APC defect.","method":"Mass spectrometry of purified APC, co-purification with epitope-tagged subunits, in vitro transcription/translation interaction assay, cell cycle FACS analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-purification plus in vitro interaction assay plus cellular phenotype; replicated by Schwickart et al. 2004","pmids":["12609981"],"is_preprint":false},{"year":2014,"finding":"Crystal structures of human APC3 alone and in complex with the C-terminal domain of APC16 reveal that APC13 (together with APC16 and CDC26) is a component of the APC/C 'Arc Lamp' sub-complex; structural and biochemical data place APC13 in proximity to the TPR subunits APC3, APC6, APC7, and APC8 that homodimerize and stack within the Arc Lamp.","method":"X-ray crystallography, biochemical mapping of subunit interactions, ubiquitination assays","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure with biochemical follow-up, but APC13's specific contacts were inferred from prior data rather than directly resolved in this study's structures","pmids":["25490258"],"is_preprint":false},{"year":2024,"finding":"The cancer-associated SF3B1-K700E mutation induces aberrant splicing of ANAPC13, inserting a 231-bp fragment into the 5′ UTR and reducing ANAPC13 protein expression. Reduced ANAPC13 in Tregs impairs Treg differentiation and inhibitory function; forced re-expression of ANAPC13 restores Treg differentiation and the ability to prevent adoptive-transfer colitis.","method":"Conditional knock-in mouse model (Sf3b1-K700E Treg-specific), RNA splicing analysis, adoptive transfer colitis assay, forced ANAPC13 expression rescue experiment","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knock-in with defined molecular mechanism (aberrant splicing) and rescue experiment with forced expression; single lab","pmids":["39303038"],"is_preprint":false},{"year":2025,"finding":"Biallelic mutations in ANAPC13 (p.D2E and p.L24R) cause oocyte maturation arrest at metaphase I in humans and in a knock-in mouse model (Anapc13M/M). Mechanistically, mutant ANAPC13 disrupts the protein composition of the APC/C, impairs APC/C ubiquitin ligase function during the metaphase I-to-anaphase I transition, and causes abnormal APC/C subunit interactions, without altering spindle assembly checkpoint dynamics. Microinjection of wild-type Anapc13 mRNA partially rescues first polar body extrusion (49%).","method":"Whole-exome sequencing, knock-in mouse model, in vitro oocyte maturation assay, proteomic analysis, molecular interaction assays with cell lines and plasmids, mRNA rescue microinjection","journal":"American journal of obstetrics and gynecology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — knock-in mouse model recapitulates human phenotype, proteomic and molecular mechanistic dissection of APC/C subunit interactions, and mRNA rescue; multiple orthogonal methods in single rigorous study","pmids":["41997520"],"is_preprint":false},{"year":2025,"finding":"Compound heterozygous missense mutations in APC13 (c.C6A and c.116_126del) found in an infertile female cause aberrant cellular localization of the ANAPC13 protein, as determined by in vitro experiments, and structural modelling predicts disrupted chemical bonds between APC13 and other APC/C subunits.","method":"Whole-exome sequencing, structural modelling, in vitro cellular localization assay","journal":"Journal of assisted reproduction and genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single case, localization data from in vitro experiment only, structural data is computational modelling","pmids":["40238067"],"is_preprint":false},{"year":1999,"finding":"In Saccharomyces cerevisiae, Swm1p (the yeast orthologue of ANAPC13) is a nuclear protein required for the completion of late sporulation events, including spore wall assembly. Swm1p is not epistatic to the Sps1p-Smk1p MAP kinase sporulation pathway, indicating it acts in a separate signal transduction pathway controlling late sporulation gene expression.","method":"Gene deletion analysis, sporulation assays, epistasis analysis, transcriptional reporter assays, nuclear localization determination","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis combined with phenotypic and localization analysis; pathway placement by exclusion via double-mutant analysis","pmids":["10022899"],"is_preprint":false},{"year":2004,"finding":"In S. cerevisiae, Swm1p (ANAPC13 yeast orthologue) is required to maintain cell wall integrity during growth at high temperature; swm1Δ cells show a 7-fold reduction in glucan synthase activity and a 3.5-fold increase in chitin content deposited delocalized across the cell wall, with the excess chitin synthesized primarily by chitin synthase III (Chs3p), as shown by the swm1 chs3 double mutant.","method":"Growth assay at restrictive temperature, electron microscopy, glucan synthase activity assay, chitin quantification, double-mutant analysis","journal":"FEMS microbiology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic activity assay and epistatic double-mutant dissection; single lab, mechanistically linked to APC/C role","pmids":["15135545"],"is_preprint":false}],"current_model":"ANAPC13 (SWM1/APC13) is a small, evolutionarily conserved core subunit of the APC/C E3 ubiquitin ligase that resides in the 'Arc Lamp' sub-complex and stabilizes the association of the TPR subunits CDC16/Cdc16 and CDC27/Cdc27 with the complex; its loss abolishes APC/C ubiquitin ligase activity in vitro and delays APC/C-dependent cell cycle transitions in vivo, and biallelic loss-of-function mutations in ANAPC13 cause oocyte maturation arrest at metaphase I in both humans and mice by impairing APC/C subunit interactions and the proteolytic program required for the metaphase I-to-anaphase I transition."},"narrative":{"mechanistic_narrative":"ANAPC13 (Swm1/Apc13) is a small, evolutionarily conserved core subunit of the anaphase-promoting complex/cyclosome (APC/C), the E3 ubiquitin ligase that drives cell cycle transitions [PMID:15060174, PMID:12609981]. Within the complex it promotes the stable association of the essential TPR subunits CDC16/Cdc16 and CDC27/Cdc23 with the APC/C, and structural mapping places APC13 in the 'Arc Lamp' sub-complex alongside APC16 and CDC26, in proximity to the homodimerizing TPR subunits APC3, APC6, APC7, and APC8 [PMID:15060174, PMID:25490258]. Loss of the subunit reduces APC/C ubiquitin ligase activity in vitro and delays APC/C-dependent cell cycle events in vivo, with deletion causing G2/M accumulation [PMID:15060174, PMID:12609981]. Biallelic loss-of-function mutations in ANAPC13 cause human and mouse oocyte maturation arrest at metaphase I by disrupting APC/C subunit composition and impairing the ubiquitin ligase activity required for the metaphase I-to-anaphase I transition, without altering spindle assembly checkpoint dynamics; wild-type mRNA partially rescues polar body extrusion [PMID:41997520]. In budding yeast the orthologue is additionally required for late sporulation and cell wall integrity, functions mechanistically tied to its APC/C role [PMID:10022899, PMID:15135545].","teleology":[{"year":1999,"claim":"Before its assignment to the APC/C, the yeast orthologue was first defined functionally as a nuclear factor needed for completion of late sporulation, establishing a developmental cell-cycle-linked role distinct from a known MAP kinase pathway.","evidence":"Gene deletion, sporulation and epistasis assays, transcriptional reporters and nuclear localization in S. cerevisiae","pmids":["10022899"],"confidence":"Medium","gaps":["Molecular identity of the pathway and biochemical activity unknown at this stage","No link yet to APC/C","Mechanism of sporulation gene control not resolved"]},{"year":2003,"claim":"The question of whether Swm1 was a bona fide APC/C component was answered by identifying it as a constitutive core subunit present across the cell cycle and in meiosis that interacts with Cdc23/APC8 and Apc5.","evidence":"Mass spectrometry of purified APC, co-purification with tagged subunits, in vitro transcription/translation interaction, FACS cell cycle analysis in budding yeast","pmids":["12609981"],"confidence":"High","gaps":["Did not establish the functional consequence for ligase activity","Specific structural contacts unresolved"]},{"year":2004,"claim":"The mechanistic role within the complex was defined: the subunit stabilizes the TPR subunits Cdc16 and Cdc27, and its loss reduces ligase activity and delays cell cycle progression, with conservation demonstrated by cross-species complementation.","evidence":"Mass spectrometry, co-purification, in vitro ubiquitin ligase reconstitution, complementation across human and fission yeast homologues, cell cycle analysis","pmids":["15060174"],"confidence":"High","gaps":["Atomic-resolution placement of the subunit not yet determined","Direct contacts with TPR subunits inferred from association assays"]},{"year":2004,"claim":"A parallel yeast study connected the subunit to cell wall integrity, showing reduced glucan synthase activity and delocalized chitin overdeposition, extending the phenotypic consequences of its loss.","evidence":"Growth assays at restrictive temperature, electron microscopy, glucan synthase and chitin quantification, swm1 chs3 double-mutant analysis","pmids":["15135545"],"confidence":"Medium","gaps":["Causal chain from APC/C function to cell wall phenotype not directly demonstrated","Single lab"]},{"year":2014,"claim":"Structural work positioned the subunit within the APC/C architecture, placing APC13 in the 'Arc Lamp' sub-complex with APC16 and CDC26 near the stacked TPR subunits.","evidence":"X-ray crystallography of human APC3 and APC3–APC16 complex, biochemical subunit-interaction mapping, ubiquitination assays","pmids":["25490258"],"confidence":"Medium","gaps":["APC13's own contacts inferred from prior data rather than directly resolved in these structures","No full-complex density for APC13"]},{"year":2024,"claim":"A disease-context role emerged: the SF3B1-K700E splicing mutation aberrantly splices ANAPC13 to reduce its protein level, impairing regulatory T cell differentiation and function, linking subunit dosage to immune phenotypes.","evidence":"Treg-specific Sf3b1-K700E knock-in mouse, RNA splicing analysis, adoptive-transfer colitis assay, forced re-expression rescue","pmids":["39303038"],"confidence":"Medium","gaps":["Mechanism connecting reduced ANAPC13 to Treg biology via APC/C not dissected","Single lab"]},{"year":2025,"claim":"The clinical and mechanistic basis of a human Mendelian phenotype was established: biallelic ANAPC13 mutations cause oocyte metaphase I arrest by disrupting APC/C composition and ligase function during the metaphase I-to-anaphase I transition.","evidence":"Whole-exome sequencing, Anapc13 knock-in mouse, in vitro oocyte maturation, proteomics, molecular interaction assays, mRNA rescue microinjection","pmids":["41997520"],"confidence":"High","gaps":["Only partial rescue achieved (49%)","Precise structural disruption of subunit contacts not resolved","Spindle checkpoint shown unaffected but downstream substrate stabilization not catalogued"]},{"year":2025,"claim":"An additional infertility case associated mutations with aberrant cellular localization of the protein and predicted disrupted inter-subunit bonds, adding candidate variants to the maturation-arrest spectrum.","evidence":"Whole-exome sequencing, in vitro localization assay, computational structural modelling in a single infertile female","pmids":["40238067"],"confidence":"Low","gaps":["Single case with no functional rescue","Localization from in vitro overexpression only","Structural prediction is computational, not experimentally resolved"]},{"year":null,"claim":"How ANAPC13 dosage and subunit-assembly defects translate into tissue-specific outcomes (oocyte arrest versus Treg dysfunction) and which APC/C substrates are differentially affected remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No substrate-level map of APC/C dysregulation across tissues","No high-resolution structure of human APC13 within the assembled complex","Tissue-specificity of phenotypes unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0]}],"complexes":["APC/C","APC/C Arc Lamp sub-complex"],"partners":["CDC16","CDC27","CDC23","APC5","APC16","CDC26"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BS18","full_name":"Anaphase-promoting complex subunit 13","aliases":["Cyclosome subunit 13"],"length_aa":74,"mass_kda":8.5,"function":"Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle (PubMed:15060174, PubMed:18485873). The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains (PubMed:15060174, PubMed:18485873). The APC/C complex catalyzes assembly of branched 'Lys-11'-/'Lys-48'-linked branched ubiquitin chains on target proteins (PubMed:29033132)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9BS18/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ANAPC13","classification":"Common Essential","n_dependent_lines":851,"n_total_lines":1208,"dependency_fraction":0.7044701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ANAPC16","stoichiometry":10.0},{"gene":"ANAPC2","stoichiometry":10.0},{"gene":"CDC16","stoichiometry":10.0},{"gene":"CDC23","stoichiometry":10.0},{"gene":"CDC26","stoichiometry":10.0},{"gene":"ANAPC4","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/ANAPC13","total_profiled":1310},"omim":[{"mim_id":"614484","title":"ANAPHASE-PROMOTING COMPLEX, SUBUNIT 13; ANAPC13","url":"https://www.omim.org/entry/614484"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ANAPC13"},"hgnc":{"alias_symbol":["SWM1","APC13","DKFZP566D193"],"prev_symbol":[]},"alphafold":{"accession":"Q9BS18","domains":[{"cath_id":"-","chopping":"32-74","consensus_level":"medium","plddt":67.6502,"start":32,"end":74}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BS18","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BS18-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BS18-F1-predicted_aligned_error_v6.png","plddt_mean":73.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANAPC13","jax_strain_url":"https://www.jax.org/strain/search?query=ANAPC13"},"sequence":{"accession":"Q9BS18","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BS18.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BS18/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BS18"}},"corpus_meta":[{"pmid":"8692845","id":"PMC_8692845","title":"An abundant 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Human and fission yeast homologues associate with APC/C subunits and complement the yeast swm1Δ phenotype.\",\n      \"method\": \"Mass spectrometry, co-purification, in vitro ubiquitin ligase assay, complementation assay, cell cycle analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro ubiquitin ligase reconstitution combined with genetic complementation across species and subunit-association assays; independently replicated across papers 4 and 5\",\n      \"pmids\": [\"15060174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Swm1 (ANAPC13) was identified as a constitutive core subunit of the budding yeast APC/C, present throughout G1, S, and M phases and in meiotic cells. Swm1 interacts with Cdc23 (APC8) and Apc5 in an in vitro transcription/translation system. Deletion of SWM1 causes slow growth and G2/M accumulation consistent with an APC defect.\",\n      \"method\": \"Mass spectrometry of purified APC, co-purification with epitope-tagged subunits, in vitro transcription/translation interaction assay, cell cycle FACS analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-purification plus in vitro interaction assay plus cellular phenotype; replicated by Schwickart et al. 2004\",\n      \"pmids\": [\"12609981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structures of human APC3 alone and in complex with the C-terminal domain of APC16 reveal that APC13 (together with APC16 and CDC26) is a component of the APC/C 'Arc Lamp' sub-complex; structural and biochemical data place APC13 in proximity to the TPR subunits APC3, APC6, APC7, and APC8 that homodimerize and stack within the Arc Lamp.\",\n      \"method\": \"X-ray crystallography, biochemical mapping of subunit interactions, ubiquitination assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure with biochemical follow-up, but APC13's specific contacts were inferred from prior data rather than directly resolved in this study's structures\",\n      \"pmids\": [\"25490258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The cancer-associated SF3B1-K700E mutation induces aberrant splicing of ANAPC13, inserting a 231-bp fragment into the 5′ UTR and reducing ANAPC13 protein expression. Reduced ANAPC13 in Tregs impairs Treg differentiation and inhibitory function; forced re-expression of ANAPC13 restores Treg differentiation and the ability to prevent adoptive-transfer colitis.\",\n      \"method\": \"Conditional knock-in mouse model (Sf3b1-K700E Treg-specific), RNA splicing analysis, adoptive transfer colitis assay, forced ANAPC13 expression rescue experiment\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knock-in with defined molecular mechanism (aberrant splicing) and rescue experiment with forced expression; single lab\",\n      \"pmids\": [\"39303038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Biallelic mutations in ANAPC13 (p.D2E and p.L24R) cause oocyte maturation arrest at metaphase I in humans and in a knock-in mouse model (Anapc13M/M). Mechanistically, mutant ANAPC13 disrupts the protein composition of the APC/C, impairs APC/C ubiquitin ligase function during the metaphase I-to-anaphase I transition, and causes abnormal APC/C subunit interactions, without altering spindle assembly checkpoint dynamics. Microinjection of wild-type Anapc13 mRNA partially rescues first polar body extrusion (49%).\",\n      \"method\": \"Whole-exome sequencing, knock-in mouse model, in vitro oocyte maturation assay, proteomic analysis, molecular interaction assays with cell lines and plasmids, mRNA rescue microinjection\",\n      \"journal\": \"American journal of obstetrics and gynecology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — knock-in mouse model recapitulates human phenotype, proteomic and molecular mechanistic dissection of APC/C subunit interactions, and mRNA rescue; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"41997520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Compound heterozygous missense mutations in APC13 (c.C6A and c.116_126del) found in an infertile female cause aberrant cellular localization of the ANAPC13 protein, as determined by in vitro experiments, and structural modelling predicts disrupted chemical bonds between APC13 and other APC/C subunits.\",\n      \"method\": \"Whole-exome sequencing, structural modelling, in vitro cellular localization assay\",\n      \"journal\": \"Journal of assisted reproduction and genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single case, localization data from in vitro experiment only, structural data is computational modelling\",\n      \"pmids\": [\"40238067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"In Saccharomyces cerevisiae, Swm1p (the yeast orthologue of ANAPC13) is a nuclear protein required for the completion of late sporulation events, including spore wall assembly. Swm1p is not epistatic to the Sps1p-Smk1p MAP kinase sporulation pathway, indicating it acts in a separate signal transduction pathway controlling late sporulation gene expression.\",\n      \"method\": \"Gene deletion analysis, sporulation assays, epistasis analysis, transcriptional reporter assays, nuclear localization determination\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis combined with phenotypic and localization analysis; pathway placement by exclusion via double-mutant analysis\",\n      \"pmids\": [\"10022899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In S. cerevisiae, Swm1p (ANAPC13 yeast orthologue) is required to maintain cell wall integrity during growth at high temperature; swm1Δ cells show a 7-fold reduction in glucan synthase activity and a 3.5-fold increase in chitin content deposited delocalized across the cell wall, with the excess chitin synthesized primarily by chitin synthase III (Chs3p), as shown by the swm1 chs3 double mutant.\",\n      \"method\": \"Growth assay at restrictive temperature, electron microscopy, glucan synthase activity assay, chitin quantification, double-mutant analysis\",\n      \"journal\": \"FEMS microbiology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic activity assay and epistatic double-mutant dissection; single lab, mechanistically linked to APC/C role\",\n      \"pmids\": [\"15135545\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANAPC13 (SWM1/APC13) is a small, evolutionarily conserved core subunit of the APC/C E3 ubiquitin ligase that resides in the 'Arc Lamp' sub-complex and stabilizes the association of the TPR subunits CDC16/Cdc16 and CDC27/Cdc27 with the complex; its loss abolishes APC/C ubiquitin ligase activity in vitro and delays APC/C-dependent cell cycle transitions in vivo, and biallelic loss-of-function mutations in ANAPC13 cause oocyte maturation arrest at metaphase I in both humans and mice by impairing APC/C subunit interactions and the proteolytic program required for the metaphase I-to-anaphase I transition.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANAPC13 (Swm1/Apc13) is a small, evolutionarily conserved core subunit of the anaphase-promoting complex/cyclosome (APC/C), the E3 ubiquitin ligase that drives cell cycle transitions [#0, #1]. Within the complex it promotes the stable association of the essential TPR subunits CDC16/Cdc16 and CDC27/Cdc23 with the APC/C, and structural mapping places APC13 in the 'Arc Lamp' sub-complex alongside APC16 and CDC26, in proximity to the homodimerizing TPR subunits APC3, APC6, APC7, and APC8 [#0, #2]. Loss of the subunit reduces APC/C ubiquitin ligase activity in vitro and delays APC/C-dependent cell cycle events in vivo, with deletion causing G2/M accumulation [#0, #1]. Biallelic loss-of-function mutations in ANAPC13 cause human and mouse oocyte maturation arrest at metaphase I by disrupting APC/C subunit composition and impairing the ubiquitin ligase activity required for the metaphase I-to-anaphase I transition, without altering spindle assembly checkpoint dynamics; wild-type mRNA partially rescues polar body extrusion [#4]. In budding yeast the orthologue is additionally required for late sporulation and cell wall integrity, functions mechanistically tied to its APC/C role [#6, #7].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Before its assignment to the APC/C, the yeast orthologue was first defined functionally as a nuclear factor needed for completion of late sporulation, establishing a developmental cell-cycle-linked role distinct from a known MAP kinase pathway.\",\n      \"evidence\": \"Gene deletion, sporulation and epistasis assays, transcriptional reporters and nuclear localization in S. cerevisiae\",\n      \"pmids\": [\"10022899\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular identity of the pathway and biochemical activity unknown at this stage\", \"No link yet to APC/C\", \"Mechanism of sporulation gene control not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The question of whether Swm1 was a bona fide APC/C component was answered by identifying it as a constitutive core subunit present across the cell cycle and in meiosis that interacts with Cdc23/APC8 and Apc5.\",\n      \"evidence\": \"Mass spectrometry of purified APC, co-purification with tagged subunits, in vitro transcription/translation interaction, FACS cell cycle analysis in budding yeast\",\n      \"pmids\": [\"12609981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the functional consequence for ligase activity\", \"Specific structural contacts unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The mechanistic role within the complex was defined: the subunit stabilizes the TPR subunits Cdc16 and Cdc27, and its loss reduces ligase activity and delays cell cycle progression, with conservation demonstrated by cross-species complementation.\",\n      \"evidence\": \"Mass spectrometry, co-purification, in vitro ubiquitin ligase reconstitution, complementation across human and fission yeast homologues, cell cycle analysis\",\n      \"pmids\": [\"15060174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution placement of the subunit not yet determined\", \"Direct contacts with TPR subunits inferred from association assays\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"A parallel yeast study connected the subunit to cell wall integrity, showing reduced glucan synthase activity and delocalized chitin overdeposition, extending the phenotypic consequences of its loss.\",\n      \"evidence\": \"Growth assays at restrictive temperature, electron microscopy, glucan synthase and chitin quantification, swm1 chs3 double-mutant analysis\",\n      \"pmids\": [\"15135545\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from APC/C function to cell wall phenotype not directly demonstrated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Structural work positioned the subunit within the APC/C architecture, placing APC13 in the 'Arc Lamp' sub-complex with APC16 and CDC26 near the stacked TPR subunits.\",\n      \"evidence\": \"X-ray crystallography of human APC3 and APC3–APC16 complex, biochemical subunit-interaction mapping, ubiquitination assays\",\n      \"pmids\": [\"25490258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"APC13's own contacts inferred from prior data rather than directly resolved in these structures\", \"No full-complex density for APC13\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A disease-context role emerged: the SF3B1-K700E splicing mutation aberrantly splices ANAPC13 to reduce its protein level, impairing regulatory T cell differentiation and function, linking subunit dosage to immune phenotypes.\",\n      \"evidence\": \"Treg-specific Sf3b1-K700E knock-in mouse, RNA splicing analysis, adoptive-transfer colitis assay, forced re-expression rescue\",\n      \"pmids\": [\"39303038\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting reduced ANAPC13 to Treg biology via APC/C not dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The clinical and mechanistic basis of a human Mendelian phenotype was established: biallelic ANAPC13 mutations cause oocyte metaphase I arrest by disrupting APC/C composition and ligase function during the metaphase I-to-anaphase I transition.\",\n      \"evidence\": \"Whole-exome sequencing, Anapc13 knock-in mouse, in vitro oocyte maturation, proteomics, molecular interaction assays, mRNA rescue microinjection\",\n      \"pmids\": [\"41997520\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Only partial rescue achieved (49%)\", \"Precise structural disruption of subunit contacts not resolved\", \"Spindle checkpoint shown unaffected but downstream substrate stabilization not catalogued\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"An additional infertility case associated mutations with aberrant cellular localization of the protein and predicted disrupted inter-subunit bonds, adding candidate variants to the maturation-arrest spectrum.\",\n      \"evidence\": \"Whole-exome sequencing, in vitro localization assay, computational structural modelling in a single infertile female\",\n      \"pmids\": [\"40238067\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single case with no functional rescue\", \"Localization from in vitro overexpression only\", \"Structural prediction is computational, not experimentally resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ANAPC13 dosage and subunit-assembly defects translate into tissue-specific outcomes (oocyte arrest versus Treg dysfunction) and which APC/C substrates are differentially affected remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No substrate-level map of APC/C dysregulation across tissues\", \"No high-resolution structure of human APC13 within the assembled complex\", \"Tissue-specificity of phenotypes unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"APC/C\",\n      \"APC/C Arc Lamp sub-complex\"\n    ],\n    \"partners\": [\n      \"CDC16\",\n      \"CDC27\",\n      \"CDC23\",\n      \"APC5\",\n      \"APC16\",\n      \"CDC26\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}