{"gene":"ANAPC7","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2021,"finding":"APC7 is a core component of the APC/C E3 ubiquitin ligase required for the recruitment and ubiquitination of APC substrates in neurons. Loss-of-function mutations in APC7 cause an intellectual disability syndrome. Proteomics of mouse brain harboring a patient-specific APC7 mutation identified Ki-67 as an APC7-dependent substrate in neurons, accumulating specifically in constitutive heterochromatin upon APC7 loss. Conditional knockout of CDH1 (but not CDC20) phenocopied Ki-67 accumulation, establishing that APC7 is specifically required for CDH1-APC (APC/C-CDH1) function in the brain.","method":"Patient genetics, conditional knockout mouse models, quantitative brain proteomics, immunofluorescence, epistasis between Cdh1 and Cdc20 knockouts","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (proteomics, conditional KO epistasis, patient mutation modeling) in a single rigorous study","pmids":["34942119"],"is_preprint":false},{"year":2024,"finding":"ANAPC7 (APC7) acts as a genetic modifier of KIF18A function in mitotic progression. Co-depletion of APC7 partially rescued the mitotic arrest induced by KIF18A depletion in cell line models, whereas co-depletion of ANAPC5 exacerbated the arrest, placing APC7 activity in opposition to KIF18A-dependent mitotic checkpoint signaling. A retroviral insertion in Anapc7 may underlie differential expression between mouse strain backgrounds sensitive or resistant to KIF18A-loss-induced germ cell depletion.","method":"Genetic screen in mouse strain backgrounds, siRNA co-depletion in cell lines with mitotic arrest readout, retroviral insertion identification","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2/3 — epistasis established by co-depletion in cell lines, supported by in vivo genetic association but single lab","pmids":["40596695","39677807"],"is_preprint":false},{"year":2003,"finding":"APC7 (Apc7) is a tetratricopeptide repeat (TPR) subunit of the human/vertebrate APC/C that is phosphorylated at mitosis-specific sites. Forty-three phospho-sites were identified on the APC, of which at least 32 are mitosis-specific and clustered in Apc1 and the TPR subunits including Apc7. CDK1-mediated phosphorylation of APC subunits (including Apc7) is sufficient for increased CDC20 binding and APC activation, whereas PLK1 phosphorylation is not.","method":"Mass spectrometry phospho-site mapping, in vitro kinase assays with CDK1 and PLK1, CDC20 binding assays, immunofluorescence with phospho-antibodies","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1/2 — in vitro kinase assays combined with MS-based site identification and functional CDC20-binding readout, replicated across conditions","pmids":["14657031"],"is_preprint":false},{"year":2010,"finding":"APC7 was identified as a previously unknown, evolutionarily conserved subunit of the human anaphase-promoting complex through tandem-affinity purification coupled to mass spectrometry and protein localization studies in the MitoCheck systematic chromosome segregation complex analysis.","method":"BAC-based gene tagging, tandem-affinity purification–mass spectrometry, protein localization","journal":"Science","confidence":"Medium","confidence_rationale":"Tier 2 — systematic TAP-MS with localization, part of large consortium effort","pmids":["20360068"],"is_preprint":false},{"year":2005,"finding":"Loss of APC7 protein expression in human invasive ductal breast carcinoma is associated with elevated histologic grade, mitotic index, Ki-67 positivity, and aneuploidy, suggesting that downregulation of the APC7 subunit disrupts APC/C E3 ubiquitin ligase activity and may contribute to tumorigenesis.","method":"Immunohistochemistry on 108 breast carcinoma specimens with clinicopathologic correlation","journal":"Breast cancer research","confidence":"Low","confidence_rationale":"Tier 3 — IHC correlation only, no direct mechanistic experiment on APC7 function","pmids":["15743504"],"is_preprint":false}],"current_model":"ANAPC7 (APC7) is a tetratricopeptide repeat (TPR)-containing core subunit of the APC/C E3 ubiquitin ligase that undergoes CDK1-dependent mitotic phosphorylation to facilitate CDC20 binding and APC/C activation; it is specifically required for CDH1-APC/C-dependent ubiquitination of substrates such as Ki-67 in post-mitotic neurons, with its loss causing neuronal heterochromatin dysregulation and an intellectual disability syndrome, and it also modulates mitotic checkpoint sensitivity in a genetic epistasis relationship with KIF18A."},"narrative":{"teleology":[{"year":2003,"claim":"Identifying mitosis-specific phosphorylation of APC/C subunits including APC7 by CDK1, and showing this phosphorylation is sufficient for CDC20 binding, established the regulatory mechanism by which the APC/C is activated at mitotic entry.","evidence":"Mass spectrometry phospho-site mapping combined with in vitro CDK1/PLK1 kinase assays and CDC20 binding assays on purified APC/C","pmids":["14657031"],"confidence":"High","gaps":["Individual contributions of APC7 phospho-sites versus other TPR subunit sites to CDC20 recruitment were not dissected","No in vivo mutagenesis of APC7 phospho-sites to confirm functional necessity"]},{"year":2005,"claim":"Correlating loss of APC7 protein in breast carcinomas with high mitotic index and aneuploidy raised the possibility that APC7 downregulation contributes to tumorigenesis, though direct causality was not tested.","evidence":"Immunohistochemistry on 108 invasive ductal breast carcinomas with clinicopathologic correlation","pmids":["15743504"],"confidence":"Low","gaps":["Correlation only; no functional rescue or knockdown experiments to establish causality","APC7 loss could be a passenger event rather than a driver","No mechanistic link between APC7 loss and the observed aneuploidy was demonstrated"]},{"year":2010,"claim":"Systematic proteomic identification of APC7 as a conserved APC/C subunit through tandem-affinity purification confirmed its stable integration into the complex and provided localization data.","evidence":"BAC-based gene tagging with tandem-affinity purification–mass spectrometry in the MitoCheck consortium","pmids":["20360068"],"confidence":"Medium","gaps":["Study was systematic rather than APC7-focused; no functional dissection of APC7 within the complex","Stoichiometry and structural position within the APC/C not resolved here"]},{"year":2021,"claim":"Demonstrating that APC7 is specifically required for CDH1-APC/C-dependent ubiquitination of Ki-67 in neurons, and that patient loss-of-function mutations cause intellectual disability with heterochromatin dysregulation, established a post-mitotic, tissue-specific role for this APC/C subunit and linked it to human disease.","evidence":"Patient genetics, conditional Apc7/Cdh1/Cdc20 knockout mouse models, quantitative brain proteomics, and immunofluorescence","pmids":["34942119"],"confidence":"High","gaps":["How APC7 selectively promotes CDH1-dependent but not CDC20-dependent substrate recognition is structurally unexplained","Whether Ki-67 accumulation is the primary driver of the intellectual disability phenotype or a marker of broader heterochromatin defects is unresolved","Whether other tissues are similarly affected by APC7 loss-of-function has not been systematically examined"]},{"year":2024,"claim":"Identifying APC7 as a genetic modifier that opposes KIF18A-dependent mitotic checkpoint signaling revealed a new axis of APC/C regulation of mitotic fidelity distinct from canonical substrate degradation.","evidence":"siRNA co-depletion in cell lines with mitotic arrest readout, supported by genetic association with retroviral insertion in mouse strain backgrounds","pmids":["40596695","39677807"],"confidence":"Medium","gaps":["Mechanism by which APC7 modulates checkpoint sensitivity (direct substrate versus indirect regulation) is unknown","Opposing effects of APC7 versus ANAPC5 co-depletion on mitotic arrest remain unexplained at a biochemical level","Retroviral insertion effect on Anapc7 expression or splicing has not been functionally validated"]},{"year":null,"claim":"Key unresolved questions include the structural basis for APC7's selective requirement in CDH1-APC/C activity, the identity of additional APC7-dependent substrates beyond Ki-67, and the molecular mechanism by which APC7 modulates mitotic checkpoint sensitivity in epistasis with KIF18A.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of APC7 in the context of the CDH1-bound APC/C is available","Full substrate repertoire of APC7-dependent ubiquitination in different tissues is uncharacterized","Direct biochemical link between APC7 and mitotic checkpoint components has not been demonstrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2]}],"complexes":["APC/C"],"partners":["CDC20","CDH1","KIF18A","ANAPC5"],"other_free_text":[]},"mechanistic_narrative":"ANAPC7 (APC7) is a tetratricopeptide repeat (TPR)-containing core subunit of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase that functions in cell-cycle progression and post-mitotic ubiquitin-dependent proteolysis. CDK1-dependent phosphorylation of APC7 and other APC/C TPR subunits during mitosis promotes CDC20 binding and APC/C activation [PMID:14657031]. In post-mitotic neurons, APC7 is specifically required for CDH1-APC/C-mediated ubiquitination of Ki-67, and loss-of-function mutations in ANAPC7 cause an intellectual disability syndrome characterized by neuronal heterochromatin dysregulation [PMID:34942119]. APC7 also modulates mitotic checkpoint sensitivity, acting as a genetic modifier in epistasis with KIF18A during mitotic progression [PMID:40596695]."},"prefetch_data":{"uniprot":{"accession":"Q9UJX3","full_name":"Anaphase-promoting complex subunit 7","aliases":["Cyclosome subunit 7"],"length_aa":565,"mass_kda":63.1,"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: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:18485873). The APC/C complex catalyzes assembly of branched 'Lys-11'-/'Lys-48'-linked branched ubiquitin chains on target proteins (PubMed:29033132). APC7 is not required for the assembly of the APC/C complex, but has an enzyme-substrate adapter activity mediating the processive ubiquitination of specific substrates (PubMed:34942119). Involved in brain development through the specific ubiquitination and clearance of MKI67 from constitutive heterochromatin after neuronal progenitors exit mitosis (PubMed:34942119)","subcellular_location":"Cytoplasm, cytoskeleton; Nucleus; Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/Q9UJX3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANAPC7","classification":"Not 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ANAPC7","url":"https://www.omim.org/entry/606949"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Microtubules","reliability":"Supported"},{"location":"Cytokinetic bridge","reliability":"Supported"},{"location":"Mitotic spindle","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ANAPC7"},"hgnc":{"alias_symbol":["APC7"],"prev_symbol":[]},"alphafold":{"accession":"Q9UJX3","domains":[{"cath_id":"1.25.40.10","chopping":"490-554","consensus_level":"medium","plddt":85.8145,"start":490,"end":554}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UJX3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UJX3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UJX3-F1-predicted_aligned_error_v6.png","plddt_mean":83.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANAPC7","jax_strain_url":"https://www.jax.org/strain/search?query=ANAPC7"},"sequence":{"accession":"Q9UJX3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UJX3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UJX3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UJX3"}},"corpus_meta":[{"pmid":"35176309","id":"PMC_35176309","title":"Circular RNA ANAPC7 Inhibits 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Conditional knockout of the APC coactivator Cdh1 (but not Cdc20) phenocopies this accumulation, establishing that APC7 is specifically required for Cdh1-APC/C activity in the brain.\",\n      \"method\": \"Patient-derived APC7 mutation knock-in mouse model, proteomics of brain tissue, conditional knockout of Cdh1 and Cdc20 in vivo\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal in vivo methods (proteomics, conditional KO of coactivators) in a single rigorous study establishing substrate and coactivator dependency\",\n      \"pmids\": [\"34942119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Deregulated neuronal Ki-67 upon APC7 loss localizes predominantly to constitutive heterochromatin, defining an essential function for APC7 and Cdh1-APC/C in neuronal heterochromatin regulation.\",\n      \"method\": \"Immunofluorescence and chromatin fractionation in mouse brain neurons with patient-specific APC7 mutation\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional consequence, supported by genetic KO data in vivo\",\n      \"pmids\": [\"34942119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Co-depletion of ANAPC7 (APC7) partially rescues mitotic arrest induced by KIF18A depletion in cell line models, while co-depletion of ANAPC5 exacerbates it, placing APC7 genetically downstream of KIF18A in the mitotic arrest pathway.\",\n      \"method\": \"siRNA co-depletion of KIF18A and ANAPC7 in cell lines with mitotic progression readout\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis by double depletion with defined mitotic phenotype, single study\",\n      \"pmids\": [\"40596695\", \"39677807\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANAPC7 (APC7) is a core structural subunit of the APC/C E3 ubiquitin ligase that is specifically required for substrate recruitment and ubiquitination by the Cdh1-APC/C complex; in neurons it targets the chromatin-associated protein Ki-67 for degradation to regulate constitutive heterochromatin, and in mitotic cells it modulates the spindle checkpoint response downstream of KIF18A.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"APC7 is a core component of the APC/C E3 ubiquitin ligase required for the recruitment and ubiquitination of APC substrates in neurons. Loss-of-function mutations in APC7 cause an intellectual disability syndrome. Proteomics of mouse brain harboring a patient-specific APC7 mutation identified Ki-67 as an APC7-dependent substrate in neurons, accumulating specifically in constitutive heterochromatin upon APC7 loss. Conditional knockout of CDH1 (but not CDC20) phenocopied Ki-67 accumulation, establishing that APC7 is specifically required for CDH1-APC (APC/C-CDH1) function in the brain.\",\n      \"method\": \"Patient genetics, conditional knockout mouse models, quantitative brain proteomics, immunofluorescence, epistasis between Cdh1 and Cdc20 knockouts\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (proteomics, conditional KO epistasis, patient mutation modeling) in a single rigorous study\",\n      \"pmids\": [\"34942119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANAPC7 (APC7) acts as a genetic modifier of KIF18A function in mitotic progression. Co-depletion of APC7 partially rescued the mitotic arrest induced by KIF18A depletion in cell line models, whereas co-depletion of ANAPC5 exacerbated the arrest, placing APC7 activity in opposition to KIF18A-dependent mitotic checkpoint signaling. A retroviral insertion in Anapc7 may underlie differential expression between mouse strain backgrounds sensitive or resistant to KIF18A-loss-induced germ cell depletion.\",\n      \"method\": \"Genetic screen in mouse strain backgrounds, siRNA co-depletion in cell lines with mitotic arrest readout, retroviral insertion identification\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — epistasis established by co-depletion in cell lines, supported by in vivo genetic association but single lab\",\n      \"pmids\": [\"40596695\", \"39677807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"APC7 (Apc7) is a tetratricopeptide repeat (TPR) subunit of the human/vertebrate APC/C that is phosphorylated at mitosis-specific sites. Forty-three phospho-sites were identified on the APC, of which at least 32 are mitosis-specific and clustered in Apc1 and the TPR subunits including Apc7. CDK1-mediated phosphorylation of APC subunits (including Apc7) is sufficient for increased CDC20 binding and APC activation, whereas PLK1 phosphorylation is not.\",\n      \"method\": \"Mass spectrometry phospho-site mapping, in vitro kinase assays with CDK1 and PLK1, CDC20 binding assays, immunofluorescence with phospho-antibodies\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro kinase assays combined with MS-based site identification and functional CDC20-binding readout, replicated across conditions\",\n      \"pmids\": [\"14657031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"APC7 was identified as a previously unknown, evolutionarily conserved subunit of the human anaphase-promoting complex through tandem-affinity purification coupled to mass spectrometry and protein localization studies in the MitoCheck systematic chromosome segregation complex analysis.\",\n      \"method\": \"BAC-based gene tagging, tandem-affinity purification–mass spectrometry, protein localization\",\n      \"journal\": \"Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic TAP-MS with localization, part of large consortium effort\",\n      \"pmids\": [\"20360068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Loss of APC7 protein expression in human invasive ductal breast carcinoma is associated with elevated histologic grade, mitotic index, Ki-67 positivity, and aneuploidy, suggesting that downregulation of the APC7 subunit disrupts APC/C E3 ubiquitin ligase activity and may contribute to tumorigenesis.\",\n      \"method\": \"Immunohistochemistry on 108 breast carcinoma specimens with clinicopathologic correlation\",\n      \"journal\": \"Breast cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — IHC correlation only, no direct mechanistic experiment on APC7 function\",\n      \"pmids\": [\"15743504\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANAPC7 (APC7) is a tetratricopeptide repeat (TPR)-containing core subunit of the APC/C E3 ubiquitin ligase that undergoes CDK1-dependent mitotic phosphorylation to facilitate CDC20 binding and APC/C activation; it is specifically required for CDH1-APC/C-dependent ubiquitination of substrates such as Ki-67 in post-mitotic neurons, with its loss causing neuronal heterochromatin dysregulation and an intellectual disability syndrome, and it also modulates mitotic checkpoint sensitivity in a genetic epistasis relationship with KIF18A.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ANAPC7 (APC7) is a core subunit of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase that is specifically required for Cdh1-dependent substrate recruitment and ubiquitination; conditional knockout of the coactivator Cdh1, but not Cdc20, phenocopies APC7 loss, establishing its selective role in Cdh1-APC/C activity [PMID:34942119]. In neurons, APC7 loss leads to accumulation of the chromatin-associated protein Ki-67 at constitutive heterochromatin, defining an essential function for Cdh1-APC/C in neuronal heterochromatin regulation [PMID:34942119]. In mitotic cells, APC7 depletion partially rescues the mitotic arrest caused by KIF18A loss, placing APC7 genetically downstream of KIF18A in the spindle checkpoint response [PMID:39677807].\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"This study resolved whether APC7 is required for all APC/C activity or only for a specific coactivator arm, showing that APC7 is selectively essential for Cdh1-APC/C-mediated substrate recruitment and ubiquitination, and identifying Ki-67 as an APC7-dependent substrate whose accumulation upon APC7 loss disrupts constitutive heterochromatin in neurons.\",\n      \"evidence\": \"Patient-derived APC7 mutation knock-in mouse model combined with brain proteomics, conditional Cdh1 and Cdc20 knockout, immunofluorescence, and chromatin fractionation in vivo\",\n      \"pmids\": [\"34942119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether APC7 contributes to Cdh1-APC/C activity in non-neuronal tissues remains untested\",\n        \"The structural basis by which APC7 selectively supports Cdh1- over Cdc20-dependent substrate recognition is unknown\",\n        \"Whether Ki-67 is the sole APC7-dependent substrate responsible for the heterochromatin phenotype has not been determined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Epistasis experiments placed APC7 downstream of the kinesin KIF18A in the mitotic arrest pathway, revealing a role for APC7 in modulating the spindle assembly checkpoint response during mitosis.\",\n      \"evidence\": \"siRNA co-depletion of KIF18A and ANAPC7 in cell lines with mitotic progression readout\",\n      \"pmids\": [\"40596695\", \"39677807\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study using siRNA co-depletion; independent confirmation is lacking\",\n        \"The biochemical mechanism linking KIF18A-dependent spindle signals to APC7-mediated substrate degradation is uncharacterized\",\n        \"Whether the mitotic role reflects Cdh1-APC/C or Cdc20-APC/C activity has not been resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How APC7 structurally discriminates between Cdh1- and Cdc20-mediated substrate engagement, and the full repertoire of APC7-dependent APC/C substrates beyond Ki-67, remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model explaining APC7's coactivator selectivity\",\n        \"Comprehensive substrate profiling across tissues and cell cycle stages has not been performed\",\n        \"Whether APC7 loss underlies a human Mendelian neurodevelopmental disorder has not been formally established by family-level genetic evidence in the timeline\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"APC/C\"],\n    \"partners\": [\"FZR1\", \"MKI67\", \"KIF18A\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ANAPC7 (APC7) is a tetratricopeptide repeat (TPR)-containing core subunit of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase that functions in cell-cycle progression and post-mitotic ubiquitin-dependent proteolysis. CDK1-dependent phosphorylation of APC7 and other APC/C TPR subunits during mitosis promotes CDC20 binding and APC/C activation [PMID:14657031]. In post-mitotic neurons, APC7 is specifically required for CDH1-APC/C-mediated ubiquitination of Ki-67, and loss-of-function mutations in ANAPC7 cause an intellectual disability syndrome characterized by neuronal heterochromatin dysregulation [PMID:34942119]. APC7 also modulates mitotic checkpoint sensitivity, acting as a genetic modifier in epistasis with KIF18A during mitotic progression [PMID:40596695].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Identifying mitosis-specific phosphorylation of APC/C subunits including APC7 by CDK1, and showing this phosphorylation is sufficient for CDC20 binding, established the regulatory mechanism by which the APC/C is activated at mitotic entry.\",\n      \"evidence\": \"Mass spectrometry phospho-site mapping combined with in vitro CDK1/PLK1 kinase assays and CDC20 binding assays on purified APC/C\",\n      \"pmids\": [\"14657031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Individual contributions of APC7 phospho-sites versus other TPR subunit sites to CDC20 recruitment were not dissected\",\n        \"No in vivo mutagenesis of APC7 phospho-sites to confirm functional necessity\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Correlating loss of APC7 protein in breast carcinomas with high mitotic index and aneuploidy raised the possibility that APC7 downregulation contributes to tumorigenesis, though direct causality was not tested.\",\n      \"evidence\": \"Immunohistochemistry on 108 invasive ductal breast carcinomas with clinicopathologic correlation\",\n      \"pmids\": [\"15743504\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Correlation only; no functional rescue or knockdown experiments to establish causality\",\n        \"APC7 loss could be a passenger event rather than a driver\",\n        \"No mechanistic link between APC7 loss and the observed aneuploidy was demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Systematic proteomic identification of APC7 as a conserved APC/C subunit through tandem-affinity purification confirmed its stable integration into the complex and provided localization data.\",\n      \"evidence\": \"BAC-based gene tagging with tandem-affinity purification–mass spectrometry in the MitoCheck consortium\",\n      \"pmids\": [\"20360068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Study was systematic rather than APC7-focused; no functional dissection of APC7 within the complex\",\n        \"Stoichiometry and structural position within the APC/C not resolved here\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that APC7 is specifically required for CDH1-APC/C-dependent ubiquitination of Ki-67 in neurons, and that patient loss-of-function mutations cause intellectual disability with heterochromatin dysregulation, established a post-mitotic, tissue-specific role for this APC/C subunit and linked it to human disease.\",\n      \"evidence\": \"Patient genetics, conditional Apc7/Cdh1/Cdc20 knockout mouse models, quantitative brain proteomics, and immunofluorescence\",\n      \"pmids\": [\"34942119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How APC7 selectively promotes CDH1-dependent but not CDC20-dependent substrate recognition is structurally unexplained\",\n        \"Whether Ki-67 accumulation is the primary driver of the intellectual disability phenotype or a marker of broader heterochromatin defects is unresolved\",\n        \"Whether other tissues are similarly affected by APC7 loss-of-function has not been systematically examined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying APC7 as a genetic modifier that opposes KIF18A-dependent mitotic checkpoint signaling revealed a new axis of APC/C regulation of mitotic fidelity distinct from canonical substrate degradation.\",\n      \"evidence\": \"siRNA co-depletion in cell lines with mitotic arrest readout, supported by genetic association with retroviral insertion in mouse strain backgrounds\",\n      \"pmids\": [\"40596695\", \"39677807\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which APC7 modulates checkpoint sensitivity (direct substrate versus indirect regulation) is unknown\",\n        \"Opposing effects of APC7 versus ANAPC5 co-depletion on mitotic arrest remain unexplained at a biochemical level\",\n        \"Retroviral insertion effect on Anapc7 expression or splicing has not been functionally validated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for APC7's selective requirement in CDH1-APC/C activity, the identity of additional APC7-dependent substrates beyond Ki-67, and the molecular mechanism by which APC7 modulates mitotic checkpoint sensitivity in epistasis with KIF18A.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of APC7 in the context of the CDH1-bound APC/C is available\",\n        \"Full substrate repertoire of APC7-dependent ubiquitination in different tissues is uncharacterized\",\n        \"Direct biochemical link between APC7 and mitotic checkpoint components has not been demonstrated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [\n      \"APC/C\"\n    ],\n    \"partners\": [\n      \"CDC20\",\n      \"CDH1\",\n      \"KIF18A\",\n      \"ANAPC5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}