{"gene":"ANAPC1","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":1994,"finding":"The mouse Tsg24 (ANAPC1 ortholog) protein (~200 kDa) is expressed uniformly during interphase but at lower levels in mitotic cell extracts, and shows sequence similarity to the Aspergillus nidulans bimE gene, a mitotic checkpoint regulator that negatively regulates entry into mitosis.","method":"Molecular cloning, antibody development, cell-cycle fractionation by Western blot","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody-based protein detection across cell-cycle stages, single lab, two orthogonal methods (cloning + Western blot)","pmids":["7929068"],"is_preprint":false},{"year":1998,"finding":"Mammalian Tsg24 (ANAPC1) exists in two forms: a soluble form associated with other APC/C components (including Cdc27) and a centromere-bound form. Both Tsg24 and Cdc27 associate with isolated mitotic chromosomes, and Tsg24 is detectable at centromeres from prophase through anaphase (or constitutively in murine cells), supporting a model where the APC/C ubiquitinates a centromere protein to regulate sister chromatid separation.","method":"Immunofluorescence, subcellular fractionation, chromosome isolation, co-immunoprecipitation","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal localization and biochemical fractionation with multiple orthogonal methods, single lab","pmids":["9418894"],"is_preprint":false},{"year":2000,"finding":"Tsg24 (ANAPC1) localizes specifically to active centromeres (including neocentromeres) during prometaphase/metaphase, and is absent from inactive centromeres on dicentric chromosomes, indicating its centromere association is functional rather than sequence-dependent.","method":"Combined immunofluorescence and FISH on human neocentromeres and dicentric chromosomes","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional centromere controls, replicated across two studies (PMID 10607828 and 11129339), two labs","pmids":["10607828","11129339"],"is_preprint":false},{"year":2001,"finding":"Human APC1 (ANAPC1) is the largest subunit of the APC/C ubiquitin ligase complex; the different APC/C subunits are expressed at fairly constant levels relative to each other across tissues and cell types, consistent with their functioning exclusively as part of the complex.","method":"Full-length cDNA sequencing, chromosomal mapping, RNA/protein expression analysis across normal and cancer cells, EST analysis","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — expression-level evidence for complex membership, single lab, no direct biochemical reconstitution of the complex","pmids":["11179667"],"is_preprint":false},{"year":2019,"finding":"Biallelic loss-of-function mutations in ANAPC1 (including a deep intronic splicing mutation activating a 95 bp pseudoexon leading to NMD and decreased ANAPC1 protein) cause Rothmund-Thomson syndrome type 1. Patient fibroblasts show decreased ANAPC1 protein levels and prolonged interphase, establishing ANAPC1 as required for normal cell-cycle progression. Heterozygous knockout mice show increased cataract incidence.","method":"Patient fibroblast studies, RT-PCR/splicing analysis, Western blot, cell-cycle duration measurement, mouse knockout model","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (splicing assay, protein quantification, cell-cycle phenotype in patient cells, mouse model), independently supported by subsequent clinical case series","pmids":["31303264"],"is_preprint":false},{"year":2023,"finding":"ANAPC1 expression is significantly decreased in osteoporotic bone and muscle tissue compared to controls, and silencing ANAPC1 in human osteosarcoma cells reduces RUNX2 expression, suggesting ANAPC1 regulates osteogenic differentiation through RUNX2. ANAPC1 expression also changes dynamically during osteogenic differentiation of human mesenchymal stem cells.","method":"qRT-PCR and Western blot on human bone/muscle tissue, siRNA knockdown in HOS cells, MSC osteogenic differentiation assay","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown experiment with RUNX2 readout, no mechanistic pathway validation beyond expression change","pmids":["37629076"],"is_preprint":false},{"year":2025,"finding":"ANAPC1 knockdown in HCT-116 colorectal cancer cells reduces proliferation and migration, increases apoptosis, and alters cell cycle distribution, consistent with ANAPC1 promoting cell cycle progression in cancer cells.","method":"siRNA knockdown, CCK-8 proliferation assay, wound healing assay, flow cytometry for cell cycle and apoptosis","journal":"Cancer control : journal of the Moffitt Cancer Center","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, standard knockdown phenotype assays without pathway mechanistic resolution","pmids":["40229946"],"is_preprint":false},{"year":2025,"finding":"ANAPC1 knockout in HCC cell lines (most significantly JHH2) inhibits cell proliferation, and highly-expressed ANAPC1 in HCC is associated with cells in the G2/M phase and increased glycolysis/gluconeogenesis activity, suggesting ANAPC1 regulates cell cycle and metabolism through ubiquitin-mediated proteolysis.","method":"CRISPR knockout in HCC cell lines, scRNA-seq cell cycle analysis, enrichment analysis","journal":"World journal of gastrointestinal oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — CRISPR growth inhibition is functional but pathway assignment relies on enrichment analysis rather than direct mechanistic experiment","pmids":["40487972"],"is_preprint":false},{"year":2014,"finding":"RelB (alternative NF-κB pathway subunit), through regulation of ANAPC1, controls the stability of p21WAF1 and p53, thereby regulating Rb activity and EZH2 expression to suppress cell senescence. ChIP analysis confirmed RelB regulation of ANAPC1 expression.","method":"siRNA knockdown of RelB, qPCR, Western blot, ChIP in primary human fibroblasts","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional knockdown with defined downstream readouts (p21, p53 stability), single lab with multiple orthogonal methods","pmids":["25255445"],"is_preprint":false}],"current_model":"ANAPC1 (TSG24/APC1) encodes the largest scaffold subunit of the APC/C E3 ubiquitin ligase complex; it localizes to active centromeres during mitosis, is required for normal cell-cycle progression through interphase (loss prolongs interphase), and biallelic loss-of-function mutations cause Rothmund-Thomson syndrome type 1, while upstream it is transcriptionally regulated by the RelB/alternative NF-κB pathway to control p21/p53 stability and senescence."},"narrative":{"mechanistic_narrative":"ANAPC1 (TSG24/APC1) encodes the largest scaffold subunit of the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that drives cell-cycle progression [PMID:11179667]. ANAPC1 exists both as a soluble pool associated with other APC/C components such as Cdc27 and as a centromere-bound pool, localizing specifically to active centromeres from prophase through anaphase—including neocentromeres but not the inactive centromere of dicentric chromosomes—indicating a function-linked rather than sequence-dependent centromere association [PMID:9418894, PMID:10607828, PMID:11129339]. Consistent with a role in cell-cycle control, the protein is expressed throughout interphase, and its loss prolongs interphase and impairs normal cell-cycle progression [PMID:7929068, PMID:31303264]. Biallelic loss-of-function mutations in ANAPC1, including a deep intronic variant activating a pseudoexon that triggers nonsense-mediated decay and reduces ANAPC1 protein, cause Rothmund-Thomson syndrome type 1 [PMID:31303264]. Upstream, ANAPC1 transcription is controlled by the alternative NF-κB subunit RelB, which through ANAPC1 governs p21 and p53 stability and downstream Rb activity and EZH2 expression to restrain cellular senescence [PMID:25255445]. Knockdown and knockout studies in osteosarcoma, colorectal, and hepatocellular cancer cells link ANAPC1 to proliferation, migration, and survival, but the molecular substrate spectrum and the biochemical basis of these phenotypes have not been characterized in the available corpus [PMID:37629076, PMID:40229946, PMID:40487972].","teleology":[{"year":1994,"claim":"Established that the ANAPC1 product is a ~200 kDa protein with cell-cycle-coupled expression and similarity to a known mitotic-entry regulator, framing it as a candidate cell-cycle control factor.","evidence":"Molecular cloning, antibody generation, and cell-cycle Western fractionation of mouse Tsg24","pmids":["7929068"],"confidence":"Medium","gaps":["No biochemical activity assigned","Complex membership not yet established","Functional consequence of expression change untested"]},{"year":1998,"claim":"Showed ANAPC1 partitions between a soluble APC/C-associated pool and a centromere-bound pool, connecting it physically to APC/C subunits and to mitotic chromosomes.","evidence":"Immunofluorescence, chromosome isolation, and co-immunoprecipitation with Cdc27 in mammalian cells","pmids":["9418894"],"confidence":"Medium","gaps":["Centromeric substrate not identified","Recruitment mechanism to centromeres unknown","Single-lab observation"]},{"year":2000,"claim":"Demonstrated that ANAPC1 centromere localization tracks centromere activity rather than DNA sequence, distinguishing functional from structural centromere targeting.","evidence":"Combined immunofluorescence/FISH on human neocentromeres and dicentric chromosomes, replicated across two labs","pmids":["10607828","11129339"],"confidence":"Medium","gaps":["Determinant of active-centromere recruitment unresolved","Functional output of centromeric ANAPC1 not directly tested"]},{"year":2001,"claim":"Defined human APC1 as the largest APC/C subunit with stoichiometric co-expression of subunits, supporting that it functions exclusively within the complex.","evidence":"Full-length cDNA sequencing, chromosomal mapping, and expression analysis across tissues and cancer cells","pmids":["11179667"],"confidence":"Low","gaps":["No direct biochemical reconstitution of the complex","Inference rests on expression correlation, not assembly assay"]},{"year":2014,"claim":"Placed ANAPC1 downstream of RelB transcriptional control, linking the alternative NF-κB pathway to p21/p53 stability, Rb activity, and senescence suppression.","evidence":"RelB siRNA knockdown, qPCR, Western blot, and ChIP in primary human fibroblasts","pmids":["25255445"],"confidence":"Medium","gaps":["Whether ANAPC1 acts via ubiquitination of p21/p53 not shown directly","Single-lab pathway","Direct substrate engagement not tested"]},{"year":2019,"claim":"Established ANAPC1 as a disease gene by showing biallelic loss-of-function causes Rothmund-Thomson syndrome type 1 and that protein reduction prolongs interphase, tying the human phenotype to a cell-cycle defect.","evidence":"Patient fibroblast splicing/Western analysis, cell-cycle duration measurement, and heterozygous knockout mouse","pmids":["31303264"],"confidence":"High","gaps":["Tissue-specific basis of RTS phenotype unexplained","Which APC/C substrates accumulate upon ANAPC1 loss not defined"]},{"year":2025,"claim":"Extended ANAPC1 function to tumor and differentiation contexts, associating its depletion with reduced proliferation/migration, altered cell-cycle distribution, and changes in osteogenic and metabolic programs.","evidence":"siRNA/CRISPR knockdown in osteosarcoma, colorectal (HCT-116), and HCC cells with proliferation, migration, apoptosis, flow-cytometry, and enrichment readouts","pmids":["37629076","40229946","40487972"],"confidence":"Low","gaps":["Pathway assignment rests on knockdown phenotypes and enrichment rather than direct mechanism","RUNX2 and metabolic links not validated mechanistically","Single-lab studies per context"]},{"year":null,"claim":"The direct substrates ubiquitinated by ANAPC1-containing APC/C in the contexts above—and the structural basis by which ANAPC1 scaffolds substrate engagement—remain undefined in the corpus.","evidence":"","pmids":[],"confidence":"Low","gaps":["No identified centromeric or senescence-pathway substrate","No structural/reconstitution data on ANAPC1 scaffolding","Mechanism linking ANAPC1 to RUNX2/metabolism unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,3]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3]}],"complexes":["APC/C"],"partners":["CDC27"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H1A4","full_name":"Anaphase-promoting complex subunit 1","aliases":["Cyclosome subunit 1","Mitotic checkpoint regulator","Testis-specific gene 24 protein"],"length_aa":1944,"mass_kda":216.5,"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: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)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9H1A4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ANAPC1","classification":"Common 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RTS3","url":"https://www.omim.org/entry/615789"},{"mim_id":"610953","title":"PIF1 5-PRIME-TO-3-PRIME DNA HELICASE; PIF1","url":"https://www.omim.org/entry/610953"},{"mim_id":"609321","title":"SAS6 CENTRIOLAR ASSEMBLY PROTEIN; SASS6","url":"https://www.omim.org/entry/609321"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ANAPC1"},"hgnc":{"alias_symbol":["MCPR","TSG24","APC1"],"prev_symbol":[]},"alphafold":{"accession":"Q9H1A4","domains":[{"cath_id":"-","chopping":"614-683_746-843","consensus_level":"medium","plddt":81.4385,"start":614,"end":843},{"cath_id":"-","chopping":"1420-1439_1454-1617","consensus_level":"medium","plddt":92.0439,"start":1420,"end":1617},{"cath_id":"-","chopping":"1864-1944","consensus_level":"medium","plddt":73.9373,"start":1864,"end":1944}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H1A4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H1A4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H1A4-F1-predicted_aligned_error_v6.png","plddt_mean":77.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANAPC1","jax_strain_url":"https://www.jax.org/strain/search?query=ANAPC1"},"sequence":{"accession":"Q9H1A4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H1A4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H1A4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H1A4"}},"corpus_meta":[{"pmid":"10607828","id":"PMC_10607828","title":"Human 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antibody development, cell-cycle fractionation by Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody-based protein detection across cell-cycle stages, single lab, two orthogonal methods (cloning + Western blot)\",\n      \"pmids\": [\"7929068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Mammalian Tsg24 (ANAPC1) exists in two forms: a soluble form associated with other APC/C components (including Cdc27) and a centromere-bound form. Both Tsg24 and Cdc27 associate with isolated mitotic chromosomes, and Tsg24 is detectable at centromeres from prophase through anaphase (or constitutively in murine cells), supporting a model where the APC/C ubiquitinates a centromere protein to regulate sister chromatid separation.\",\n      \"method\": \"Immunofluorescence, subcellular fractionation, chromosome isolation, co-immunoprecipitation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal localization and biochemical fractionation with multiple orthogonal methods, single lab\",\n      \"pmids\": [\"9418894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Tsg24 (ANAPC1) localizes specifically to active centromeres (including neocentromeres) during prometaphase/metaphase, and is absent from inactive centromeres on dicentric chromosomes, indicating its centromere association is functional rather than sequence-dependent.\",\n      \"method\": \"Combined immunofluorescence and FISH on human neocentromeres and dicentric chromosomes\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional centromere controls, replicated across two studies (PMID 10607828 and 11129339), two labs\",\n      \"pmids\": [\"10607828\", \"11129339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human APC1 (ANAPC1) is the largest subunit of the APC/C ubiquitin ligase complex; the different APC/C subunits are expressed at fairly constant levels relative to each other across tissues and cell types, consistent with their functioning exclusively as part of the complex.\",\n      \"method\": \"Full-length cDNA sequencing, chromosomal mapping, RNA/protein expression analysis across normal and cancer cells, EST analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — expression-level evidence for complex membership, single lab, no direct biochemical reconstitution of the complex\",\n      \"pmids\": [\"11179667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Biallelic loss-of-function mutations in ANAPC1 (including a deep intronic splicing mutation activating a 95 bp pseudoexon leading to NMD and decreased ANAPC1 protein) cause Rothmund-Thomson syndrome type 1. Patient fibroblasts show decreased ANAPC1 protein levels and prolonged interphase, establishing ANAPC1 as required for normal cell-cycle progression. Heterozygous knockout mice show increased cataract incidence.\",\n      \"method\": \"Patient fibroblast studies, RT-PCR/splicing analysis, Western blot, cell-cycle duration measurement, mouse knockout model\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (splicing assay, protein quantification, cell-cycle phenotype in patient cells, mouse model), independently supported by subsequent clinical case series\",\n      \"pmids\": [\"31303264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ANAPC1 expression is significantly decreased in osteoporotic bone and muscle tissue compared to controls, and silencing ANAPC1 in human osteosarcoma cells reduces RUNX2 expression, suggesting ANAPC1 regulates osteogenic differentiation through RUNX2. ANAPC1 expression also changes dynamically during osteogenic differentiation of human mesenchymal stem cells.\",\n      \"method\": \"qRT-PCR and Western blot on human bone/muscle tissue, siRNA knockdown in HOS cells, MSC osteogenic differentiation assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown experiment with RUNX2 readout, no mechanistic pathway validation beyond expression change\",\n      \"pmids\": [\"37629076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ANAPC1 knockdown in HCT-116 colorectal cancer cells reduces proliferation and migration, increases apoptosis, and alters cell cycle distribution, consistent with ANAPC1 promoting cell cycle progression in cancer cells.\",\n      \"method\": \"siRNA knockdown, CCK-8 proliferation assay, wound healing assay, flow cytometry for cell cycle and apoptosis\",\n      \"journal\": \"Cancer control : journal of the Moffitt Cancer Center\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, standard knockdown phenotype assays without pathway mechanistic resolution\",\n      \"pmids\": [\"40229946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ANAPC1 knockout in HCC cell lines (most significantly JHH2) inhibits cell proliferation, and highly-expressed ANAPC1 in HCC is associated with cells in the G2/M phase and increased glycolysis/gluconeogenesis activity, suggesting ANAPC1 regulates cell cycle and metabolism through ubiquitin-mediated proteolysis.\",\n      \"method\": \"CRISPR knockout in HCC cell lines, scRNA-seq cell cycle analysis, enrichment analysis\",\n      \"journal\": \"World journal of gastrointestinal oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — CRISPR growth inhibition is functional but pathway assignment relies on enrichment analysis rather than direct mechanistic experiment\",\n      \"pmids\": [\"40487972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RelB (alternative NF-κB pathway subunit), through regulation of ANAPC1, controls the stability of p21WAF1 and p53, thereby regulating Rb activity and EZH2 expression to suppress cell senescence. ChIP analysis confirmed RelB regulation of ANAPC1 expression.\",\n      \"method\": \"siRNA knockdown of RelB, qPCR, Western blot, ChIP in primary human fibroblasts\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional knockdown with defined downstream readouts (p21, p53 stability), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25255445\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANAPC1 (TSG24/APC1) encodes the largest scaffold subunit of the APC/C E3 ubiquitin ligase complex; it localizes to active centromeres during mitosis, is required for normal cell-cycle progression through interphase (loss prolongs interphase), and biallelic loss-of-function mutations cause Rothmund-Thomson syndrome type 1, while upstream it is transcriptionally regulated by the RelB/alternative NF-κB pathway to control p21/p53 stability and senescence.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANAPC1 (TSG24/APC1) encodes the largest scaffold subunit of the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that drives cell-cycle progression [#3]. ANAPC1 exists both as a soluble pool associated with other APC/C components such as Cdc27 and as a centromere-bound pool, localizing specifically to active centromeres from prophase through anaphase—including neocentromeres but not the inactive centromere of dicentric chromosomes—indicating a function-linked rather than sequence-dependent centromere association [#1, #2]. Consistent with a role in cell-cycle control, the protein is expressed throughout interphase, and its loss prolongs interphase and impairs normal cell-cycle progression [#0, #4]. Biallelic loss-of-function mutations in ANAPC1, including a deep intronic variant activating a pseudoexon that triggers nonsense-mediated decay and reduces ANAPC1 protein, cause Rothmund-Thomson syndrome type 1 [#4]. Upstream, ANAPC1 transcription is controlled by the alternative NF-\\u03baB subunit RelB, which through ANAPC1 governs p21 and p53 stability and downstream Rb activity and EZH2 expression to restrain cellular senescence [#8]. Knockdown and knockout studies in osteosarcoma, colorectal, and hepatocellular cancer cells link ANAPC1 to proliferation, migration, and survival, but the molecular substrate spectrum and the biochemical basis of these phenotypes have not been characterized in the available corpus [#5, #6, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established that the ANAPC1 product is a ~200 kDa protein with cell-cycle-coupled expression and similarity to a known mitotic-entry regulator, framing it as a candidate cell-cycle control factor.\",\n      \"evidence\": \"Molecular cloning, antibody generation, and cell-cycle Western fractionation of mouse Tsg24\",\n      \"pmids\": [\"7929068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No biochemical activity assigned\", \"Complex membership not yet established\", \"Functional consequence of expression change untested\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed ANAPC1 partitions between a soluble APC/C-associated pool and a centromere-bound pool, connecting it physically to APC/C subunits and to mitotic chromosomes.\",\n      \"evidence\": \"Immunofluorescence, chromosome isolation, and co-immunoprecipitation with Cdc27 in mammalian cells\",\n      \"pmids\": [\"9418894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Centromeric substrate not identified\", \"Recruitment mechanism to centromeres unknown\", \"Single-lab observation\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated that ANAPC1 centromere localization tracks centromere activity rather than DNA sequence, distinguishing functional from structural centromere targeting.\",\n      \"evidence\": \"Combined immunofluorescence/FISH on human neocentromeres and dicentric chromosomes, replicated across two labs\",\n      \"pmids\": [\"10607828\", \"11129339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinant of active-centromere recruitment unresolved\", \"Functional output of centromeric ANAPC1 not directly tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined human APC1 as the largest APC/C subunit with stoichiometric co-expression of subunits, supporting that it functions exclusively within the complex.\",\n      \"evidence\": \"Full-length cDNA sequencing, chromosomal mapping, and expression analysis across tissues and cancer cells\",\n      \"pmids\": [\"11179667\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical reconstitution of the complex\", \"Inference rests on expression correlation, not assembly assay\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed ANAPC1 downstream of RelB transcriptional control, linking the alternative NF-\\u03baB pathway to p21/p53 stability, Rb activity, and senescence suppression.\",\n      \"evidence\": \"RelB siRNA knockdown, qPCR, Western blot, and ChIP in primary human fibroblasts\",\n      \"pmids\": [\"25255445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ANAPC1 acts via ubiquitination of p21/p53 not shown directly\", \"Single-lab pathway\", \"Direct substrate engagement not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established ANAPC1 as a disease gene by showing biallelic loss-of-function causes Rothmund-Thomson syndrome type 1 and that protein reduction prolongs interphase, tying the human phenotype to a cell-cycle defect.\",\n      \"evidence\": \"Patient fibroblast splicing/Western analysis, cell-cycle duration measurement, and heterozygous knockout mouse\",\n      \"pmids\": [\"31303264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific basis of RTS phenotype unexplained\", \"Which APC/C substrates accumulate upon ANAPC1 loss not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended ANAPC1 function to tumor and differentiation contexts, associating its depletion with reduced proliferation/migration, altered cell-cycle distribution, and changes in osteogenic and metabolic programs.\",\n      \"evidence\": \"siRNA/CRISPR knockdown in osteosarcoma, colorectal (HCT-116), and HCC cells with proliferation, migration, apoptosis, flow-cytometry, and enrichment readouts\",\n      \"pmids\": [\"37629076\", \"40229946\", \"40487972\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway assignment rests on knockdown phenotypes and enrichment rather than direct mechanism\", \"RUNX2 and metabolic links not validated mechanistically\", \"Single-lab studies per context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct substrates ubiquitinated by ANAPC1-containing APC/C in the contexts above—and the structural basis by which ANAPC1 scaffolds substrate engagement—remain undefined in the corpus.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No identified centromeric or senescence-pathway substrate\", \"No structural/reconstitution data on ANAPC1 scaffolding\", \"Mechanism linking ANAPC1 to RUNX2/metabolism unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\"APC/C\"],\n    \"partners\": [\"CDC27\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}