{"gene":"CDC26","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1996,"finding":"CDC26 (Cdc26p) is a small heat-inducible subunit of the anaphase-promoting complex (APC/cyclosome) in Saccharomyces cerevisiae, a 36S particle functioning as a cell cycle-regulated ubiquitin-protein ligase required for entry into anaphase and B-type cyclin proteolysis.","method":"Biochemical purification and subunit identification of the yeast APC complex","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct biochemical identification of subunit in purified complex, replicated across multiple subsequent studies","pmids":["8895471"],"is_preprint":false},{"year":1997,"finding":"Mutations in CDC26 prevent mitotic cyclin (Clb2) proteolysis in budding yeast, and Cdc26 associates in vivo with Doc1, Cdc16, Cdc23, and Cdc27, with the majority co-sedimenting at 20S on sucrose gradients, confirming it as an APC component.","method":"Temperature-sensitive mutant analysis, in vivo co-immunoprecipitation, sucrose gradient sedimentation","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP and sedimentation with multiple APC subunits, loss-of-function phenotype established","pmids":["9348530"],"is_preprint":false},{"year":1999,"finding":"In budding yeast, cell cycle progression of bub2 cells in the presence of nocodazole requires the Cdc26 APC subunit, placing CDC26 in a pathway distinct from the Mad2 checkpoint branch; Cdc26 is specifically required for Bub2-dependent (but not Mad2-dependent) mitotic arrest bypass.","method":"Genetic epistasis using double mutants (bub2 cdc26, mad2 cdc26) treated with nocodazole; DNA re-replication assay","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic epistasis in budding yeast, single lab but multiple mutant combinations tested","pmids":["10352016"],"is_preprint":false},{"year":1997,"finding":"In fission yeast, the Cdc26 orthologue Hcn1 can restore the assembly of the 20S APC/cyclosome when the cut9 mutant assembly is impaired, indicating a role in stabilizing or assembling the APC/C complex.","method":"Genetic suppression: elevated Hcn1 levels rescue cut9 mutant APC assembly defect; sucrose gradient analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue experiment with complex assembly readout, single lab","pmids":["9264466"],"is_preprint":false},{"year":2000,"finding":"CDC26 was identified by mass spectrometry as a subunit of the human APC, confirming its conservation from yeast to vertebrates.","method":"Mass spectrometric identification of APC subunits from purified human APC","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry from purified human complex, single lab","pmids":["10922056"],"is_preprint":false},{"year":2009,"finding":"CDC26 stabilizes the structure of APC6 (a core TPR subunit of the APC/C) through an intermolecular TPR mimic composed of one helix from each protein; CDC26-APC6 association is required for APC assembly.","method":"Biophysical analysis, crystal structure determination, genetic studies","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with biophysical and genetic validation, directly establishes molecular mechanism of CDC26-APC6 interaction","pmids":["19668213"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of S. pombe Cut9 (Cdc16/APC6) in complex with Hcn1 (Cdc26 orthologue) reveals that Cdc16/Cut9 is a contiguous TPR superhelix of 14 TPR units; the C-terminal TPR block interacts with Hcn1, and the acetylated N-terminal Met of Hcn1 is enclosed within a chamber in the Cut9 TPR superhelix, making the N-acetyl-Met degron inaccessible to the Doa10 E3 ubiquitin ligase and thereby protecting Hcn1/Cdc26 from ubiquitin-dependent degradation.","method":"Crystal structure determination of Cut9-Hcn1 complex","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structure providing mechanistic explanation for CDC26 stability and its interaction with APC6","pmids":["20924356"],"is_preprint":false},{"year":2015,"finding":"LATS1 and LATS2 directly phosphorylate CDC26 at Thr7 (T7) in human cells; this phosphorylation reduces the interaction of CDC26 with APC6, alters APC/C assembly as measured by gel filtration, and a phosphomimetic T7D mutant of CDC26 promotes ubiquitination of polo-like kinase 1 (a known APC/C substrate).","method":"In vitro kinase assay (LATS1 phosphorylates CDC26 T7), siRNA knockdown of LATS1/LATS2 in HeLa cells, co-immunoprecipitation of CDC26 with APC6, gel filtration of APC/C subunits, ubiquitination assay with T7D mutant","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay, mutagenesis, co-IP, ubiquitination assay; multiple orthogonal methods in single lab","pmids":["25723520"],"is_preprint":false},{"year":2006,"finding":"Loss-of-function mutations in zebrafish cdc26 result in mitotic arrest followed by apoptosis in dividing cells, and improper re-entry into the cell cycle in quiescent/differentiated cells, demonstrating APC/C requirement in both dividing and non-dividing vertebrate cells.","method":"Zebrafish genetic mutant analysis; phenotypic characterization of cdc26 loss-of-function","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined loss-of-function phenotype in vertebrate model organism with two distinct cellular readouts, single lab","pmids":["17141209"],"is_preprint":false},{"year":2007,"finding":"C. elegans B0511.9 (CDC-26 orthologue) shares N-terminal sequence conservation with Cdc26 orthologues, and strong RNAi inhibition causes metaphase I arrest in meiosis, phenocopying APC/C mutants; B0511.9 functionally complements the temperature-sensitive growth defect of a yeast cdc26Δ mutant.","method":"RNAi phenotypic analysis in C. elegans embryos, functional complementation of yeast cdc26Δ","journal":"BMC developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cross-species functional rescue plus RNAi phenotype, two orthogonal methods, single lab","pmids":["17374146"],"is_preprint":false},{"year":2019,"finding":"In Arabidopsis, AtCDC26 (encoded by a uORF within the AtTTM3 transcript) is part of the plant APC/C, regulates accumulation of APC/C target proteins, and controls cell division, growth, and embryo development; AtTTM3 coordinates AtCDC26 translation by recruiting the transcript into polysomes.","method":"Loss-of-function mutant analysis, immunoprecipitation to show APC/C membership, western blotting for APC/C target protein levels, polysome profiling","journal":"Nature plants","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods including co-IP for APC/C membership and polysome analysis, single lab, plant ortholog","pmids":["30737513"],"is_preprint":false},{"year":2024,"finding":"A homozygous missense mutation in APC12/CDC26 (p.R8H) disrupts the interaction between APC12 and APC6 and impairs APC/C-mediated Securin ubiquitination, causing meiotic metaphase I arrest in oocytes and female infertility; knockdown of APC12 in mouse oocytes and Apc12+/- mice recapitulate this arrest phenotype.","method":"Whole-exome sequencing, oocyte microinjection of mutant cRNA, co-immunoprecipitation (APC12–APC6 interaction), western blotting (Securin accumulation), siRNA knockdown in mouse oocytes, Apc12+/- mouse model, rescue by Apc12 cRNA injection","journal":"American journal of obstetrics and gynecology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (co-IP, ubiquitination assay, mouse KO model, rescue experiment) establishing mechanism of disease-causing mutation","pmids":["39542389"],"is_preprint":false},{"year":2021,"finding":"CDC26 protein levels are decreased in aged human and mouse oocytes, and loss of CDC26 is associated with increased aneuploidy during oocyte maturation; overexpression of CDC26 partially rescues oocyte aging defects including spindle and chromosomal abnormalities.","method":"Single-cell RNA-seq, immunocytochemistry, lentiviral overexpression in human oocytes, mouse oocyte in vitro maturation with CDC26 manipulation","journal":"Human reproduction","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function and rescue experiments with defined phenotypic readouts (aneuploidy, maturation rates), single lab, lacks direct molecular mechanism beyond APC/C membership","pmids":["34590680"],"is_preprint":false},{"year":2025,"finding":"CDC26 overexpression in human pancreatic ductal adenocarcinoma cells promotes ferroptosis by enhancing ROS and lipid peroxidation; mechanistically, CDC26 promotes ubiquitin-mediated degradation of SLC7A11 (a key ferroptosis inhibitor) and indirectly inhibits the cell cycle, sensitizing cells to ferroptosis.","method":"CDC26 overexpression experiments, ROS and lipid peroxidation assays, ubiquitination assay for SLC7A11, cell proliferation and invasion assays","journal":"Clinical and experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — single lab, mechanistic claim for SLC7A11 ubiquitination based on overexpression and ubiquitination assay; functional phenotype established but molecular detail limited","pmids":["41249642"],"is_preprint":false},{"year":1992,"finding":"The CDC26 gene in S. cerevisiae is required for cell growth only at high temperature; disruption of the gene confers thermosensitive growth, and the CDC26 gene is the same locus as SCD26 (a dosage-dependent suppressor of cdc26).","method":"Gene disruption, cloning and sequencing, complementation analysis, identification of nonsense mutation in cdc26-1","journal":"Molecular & general genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic analysis with gene disruption and sequencing, defining essential function at elevated temperature","pmids":["1736102"],"is_preprint":false}],"current_model":"CDC26 (APC12/ANAPC12) is a conserved small subunit of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase that stabilizes the TPR subunit APC6 through an intermolecular TPR-mimic interaction, is required for proper APC/C assembly, and is phosphorylated by LATS1/2 at Thr7 to modulate its interaction with APC6 and APC/C assembly state; loss of CDC26 impairs APC/C-mediated ubiquitination of substrates such as Securin and cyclin B, causing mitotic/meiotic arrest, and CDC26 also promotes ferroptosis in cancer cells by facilitating ubiquitin-mediated degradation of SLC7A11."},"narrative":{"mechanistic_narrative":"CDC26 (APC12/ANAPC12) is a small, conserved subunit of the anaphase-promoting complex/cyclosome (APC/C), the cell cycle-regulated ubiquitin-protein ligase required for entry into anaphase and proteolysis of B-type cyclins [PMID:8895471, PMID:9348530, PMID:10922056]. Within the complex it acts as a structural stabilizer of the core TPR subunit APC6 (Cdc16/Cut9): one helix from each protein forms an intermolecular TPR mimic that is required for proper APC/C assembly, and burial of CDC26's acetylated N-terminal methionine within the APC6 TPR superhelix shields an N-degron that would otherwise target CDC26 for degradation [PMID:19668213, PMID:20924356]. Loss of CDC26 prevents APC/C-mediated ubiquitination of substrates including mitotic cyclins, Securin, and Polo-like kinase 1, blocking cyclin proteolysis and producing mitotic or meiotic metaphase arrest across yeast, zebrafish, C. elegans, plant, and mammalian systems [PMID:9348530, PMID:25723520, PMID:17141209, PMID:17374146, PMID:30737513, PMID:39542389]. CDC26 activity is regulated by LATS1/2, which directly phosphorylate it at Thr7 to weaken the APC6 interaction and reshape APC/C assembly [PMID:25723520]. In human oocytes, a homozygous APC12/CDC26 p.R8H mutation disrupts the APC12-APC6 interaction and impairs Securin ubiquitination, causing meiotic metaphase I arrest and female infertility [PMID:39542389]. Beyond its APC/C role, CDC26 promotes ferroptosis in pancreatic cancer cells by facilitating ubiquitin-mediated degradation of the ferroptosis inhibitor SLC7A11 [PMID:41249642].","teleology":[{"year":1992,"claim":"Established CDC26 as a genetically defined locus whose product is required for cell growth specifically at elevated temperature, the first functional handle on the gene.","evidence":"Gene disruption, cloning, sequencing, and complementation in S. cerevisiae","pmids":["1736102"],"confidence":"Medium","gaps":["No molecular function or biochemical role identified","Temperature-dependent essentiality mechanism unexplained"]},{"year":1996,"claim":"Placed CDC26 inside the APC/cyclosome by identifying it as a subunit of the purified ubiquitin-ligase particle, defining its molecular context.","evidence":"Biochemical purification and subunit identification of the yeast APC complex","pmids":["8895471"],"confidence":"High","gaps":["Stoichiometry and structural role within the complex not defined","Substrate specificity contribution unknown"]},{"year":1997,"claim":"Confirmed CDC26 as an integral APC component and linked its loss to a failure of mitotic cyclin proteolysis, connecting the subunit to ubiquitin-dependent cell cycle control.","evidence":"Temperature-sensitive mutant analysis, in vivo co-IP with Doc1/Cdc16/Cdc23/Cdc27, and sucrose gradient sedimentation in budding yeast","pmids":["9348530"],"confidence":"High","gaps":["Direct contribution to catalysis vs assembly not separated","Which subunit CDC26 contacts not resolved"]},{"year":1997,"claim":"Showed CDC26 functions in APC/C assembly by demonstrating its fission yeast orthologue restores 20S complex assembly in a cut9 (APC6) mutant, foreshadowing the CDC26-APC6 relationship.","evidence":"Genetic suppression and sucrose gradient analysis of Hcn1 rescue of cut9 in S. pombe","pmids":["9264466"],"confidence":"Medium","gaps":["Molecular basis of assembly stabilization unknown","Single-lab genetic readout"]},{"year":1999,"claim":"Defined CDC26's checkpoint context, showing it is required for Bub2-dependent but not Mad2-dependent mitotic arrest bypass, separating its pathway from the spindle assembly checkpoint branch.","evidence":"Genetic epistasis with double mutants and DNA re-replication assays in budding yeast","pmids":["10352016"],"confidence":"Medium","gaps":["Mechanistic link between CDC26/APC and Bub2 not defined","Restricted to budding yeast"]},{"year":2000,"claim":"Demonstrated conservation of CDC26 as an APC subunit in humans, extending its function from yeast to vertebrates.","evidence":"Mass spectrometric identification of subunits from purified human APC","pmids":["10922056"],"confidence":"Medium","gaps":["Human-specific functional role not tested","Regulation in human cells unaddressed"]},{"year":2006,"claim":"Established the vertebrate requirement for CDC26 in both proliferating and quiescent cells, showing loss causes mitotic arrest with apoptosis and aberrant cell cycle re-entry.","evidence":"Zebrafish cdc26 loss-of-function mutant phenotyping","pmids":["17141209"],"confidence":"Medium","gaps":["Molecular substrate-level mechanism not addressed","Cause of aberrant re-entry in differentiated cells unclear"]},{"year":2007,"claim":"Confirmed functional conservation across metazoa by showing the C. elegans orthologue causes meiotic metaphase I arrest on depletion and complements a yeast cdc26 deletion.","evidence":"RNAi phenotyping in C. elegans embryos and cross-species yeast complementation","pmids":["17374146"],"confidence":"Medium","gaps":["Meiotic substrate specificity not defined","Single-lab study"]},{"year":2009,"claim":"Resolved CDC26's structural role: it stabilizes APC6 via an intermolecular TPR mimic in which each protein contributes one helix, an interaction required for complex assembly.","evidence":"Crystal structure, biophysics, and genetic studies of CDC26-APC6","pmids":["19668213"],"confidence":"High","gaps":["Whether CDC26 contributes beyond APC6 stabilization unresolved","Regulation of the interaction not addressed"]},{"year":2010,"claim":"Explained CDC26 protein stability by showing its acetylated N-terminal methionine is sequestered within the APC6 TPR superhelix, shielding an N-degron from the Doa10 E3 ligase.","evidence":"Crystal structure of S. pombe Cut9-Hcn1 complex","pmids":["20924356"],"confidence":"High","gaps":["Whether degron shielding operates identically in humans not tested","Turnover dynamics of free vs assembled CDC26 unmeasured"]},{"year":2015,"claim":"Identified a regulatory input on CDC26: LATS1/2 directly phosphorylate Thr7 to weaken the APC6 interaction and alter APC/C assembly, modulating substrate ubiquitination.","evidence":"In vitro kinase assay, LATS1/2 knockdown, co-IP, gel filtration, and PLK1 ubiquitination assay with a T7D phosphomimetic in human cells","pmids":["25723520"],"confidence":"High","gaps":["Cellular contexts where this phosphorylation operates not mapped","Quantitative effect on global APC/C output unknown"]},{"year":2019,"claim":"Extended CDC26 function to plants and revealed translational control, showing AtCDC26 is encoded by a uORF whose translation is coordinated by AtTTM3 and is required for APC/C function in development.","evidence":"Loss-of-function mutants, co-IP for APC/C membership, target protein westerns, and polysome profiling in Arabidopsis","pmids":["30737513"],"confidence":"Medium","gaps":["Whether uORF-based regulation occurs outside plants unknown","Mechanism of TTM3-mediated polysome recruitment not detailed"]},{"year":2021,"claim":"Linked CDC26 to oocyte aging, showing declining CDC26 correlates with aneuploidy and that overexpression partially rescues spindle and chromosomal defects.","evidence":"Single-cell RNA-seq, immunocytochemistry, and lentiviral CDC26 manipulation in human and mouse oocytes","pmids":["34590680"],"confidence":"Medium","gaps":["Direct molecular mechanism beyond APC/C membership not established","Cause of age-related CDC26 decline unknown"]},{"year":2024,"claim":"Established CDC26 as a human disease gene, showing a homozygous p.R8H mutation disrupts APC12-APC6 binding and Securin ubiquitination, causing meiotic arrest and female infertility.","evidence":"Whole-exome sequencing, oocyte cRNA microinjection, co-IP, Securin westerns, mouse knockdown and Apc12+/- model with cRNA rescue","pmids":["39542389"],"confidence":"High","gaps":["Penetrance and broader phenotypic spectrum in patients not defined","Whether other APC/C substrates are affected not fully mapped"]},{"year":2025,"claim":"Uncovered a cancer-relevant CDC26 function, showing it promotes ferroptosis in pancreatic cancer cells by facilitating ubiquitin-mediated degradation of SLC7A11.","evidence":"CDC26 overexpression, ROS and lipid peroxidation assays, and SLC7A11 ubiquitination assay in PDAC cells","pmids":["41249642"],"confidence":"Medium","gaps":["Whether SLC7A11 degradation is APC/C-dependent not established","Single-lab, overexpression-based mechanism without loss-of-function validation"]},{"year":null,"claim":"How CDC26 regulation (e.g. LATS-dependent phosphorylation) and its newly described ferroptosis/SLC7A11 role integrate with canonical APC/C cell cycle function across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No reconstitution linking SLC7A11 degradation to APC/C activity","Tissue-specific physiological consequences of CDC26 regulation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,11,13]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[5,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,5,7]}],"localization":[],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,8,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,7,11]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[13]}],"complexes":["APC/C (anaphase-promoting complex/cyclosome)"],"partners":["APC6","CDC16","CDC23","CDC27","DOC1","LATS1","LATS2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NHZ8","full_name":"Anaphase-promoting complex subunit CDC26","aliases":["Anaphase-promoting complex subunit 12","APC12","Cell division cycle protein 26 homolog"],"length_aa":85,"mass_kda":9.8,"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). May recruit the E2 ubiquitin-conjugating enzymes to the complex (PubMed:18485873)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8NHZ8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CDC26","classification":"Common Essential","n_dependent_lines":1084,"n_total_lines":1208,"dependency_fraction":0.8973509933774835},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000176386","cell_line_id":"CID000229","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"ANAPC16","stoichiometry":10.0},{"gene":"ANAPC4","stoichiometry":10.0},{"gene":"CDC16","stoichiometry":10.0},{"gene":"CDC23","stoichiometry":10.0},{"gene":"ANAPC7","stoichiometry":10.0},{"gene":"ANAPC13","stoichiometry":10.0},{"gene":"CDC27","stoichiometry":10.0},{"gene":"ANAPC10","stoichiometry":4.0},{"gene":"ANAPC1","stoichiometry":4.0},{"gene":"ANAPC5","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000229","total_profiled":1310},"omim":[{"mim_id":"614533","title":"CELL DIVISION CYCLE 26; CDC26","url":"https://www.omim.org/entry/614533"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CDC26"},"hgnc":{"alias_symbol":["APC12","ANAPC12"],"prev_symbol":["C9orf17"]},"alphafold":{"accession":"Q8NHZ8","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NHZ8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NHZ8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NHZ8-F1-predicted_aligned_error_v6.png","plddt_mean":73.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDC26","jax_strain_url":"https://www.jax.org/strain/search?query=CDC26"},"sequence":{"accession":"Q8NHZ8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NHZ8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NHZ8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NHZ8"}},"corpus_meta":[{"pmid":"8895471","id":"PMC_8895471","title":"Identification of subunits of the anaphase-promoting complex of Saccharomyces cerevisiae.","date":"1996","source":"Science (New 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open reading frames in a 30.8 kb region of the right arm of chromosome VI from Saccharomyces cerevisiae.","date":"1996","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/8686381","citation_count":3,"is_preprint":false},{"pmid":"39542389","id":"PMC_39542389","title":"Homozygous missense variations of APC12 cause meiotic metaphase I arrest in oocytes and female infertility.","date":"2024","source":"American journal of obstetrics and gynecology","url":"https://pubmed.ncbi.nlm.nih.gov/39542389","citation_count":2,"is_preprint":false},{"pmid":"39055932","id":"PMC_39055932","title":"Atypical cadherin, Fat2, regulates axon terminal organization in the developing Drosophila olfactory receptor neurons.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/39055932","citation_count":2,"is_preprint":false},{"pmid":"41249642","id":"PMC_41249642","title":"CDC26 facilitates ferroptosis through SLC7A11 degradation and cell cycle arrest.","date":"2025","source":"Clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41249642","citation_count":1,"is_preprint":false},{"pmid":"39859203","id":"PMC_39859203","title":"Onvansertib and Navitoclax Combination as a New Therapeutic Option for Mucinous Ovarian Carcinoma.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39859203","citation_count":1,"is_preprint":false},{"pmid":"41997520","id":"PMC_41997520","title":"Biallelic mutations in ANAPC13 cause female infertility characterized by oocyte maturation arrest both in humans and mice.","date":"2026","source":"American journal of obstetrics and gynecology","url":"https://pubmed.ncbi.nlm.nih.gov/41997520","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15396,"output_tokens":3625,"usd":0.050281,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11276,"output_tokens":4320,"usd":0.08219,"stage2_stop_reason":"end_turn"},"total_usd":0.132471,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"CDC26 (Cdc26p) is a small heat-inducible subunit of the anaphase-promoting complex (APC/cyclosome) in Saccharomyces cerevisiae, a 36S particle functioning as a cell cycle-regulated ubiquitin-protein ligase required for entry into anaphase and B-type cyclin proteolysis.\",\n      \"method\": \"Biochemical purification and subunit identification of the yeast APC complex\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct biochemical identification of subunit in purified complex, replicated across multiple subsequent studies\",\n      \"pmids\": [\"8895471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Mutations in CDC26 prevent mitotic cyclin (Clb2) proteolysis in budding yeast, and Cdc26 associates in vivo with Doc1, Cdc16, Cdc23, and Cdc27, with the majority co-sedimenting at 20S on sucrose gradients, confirming it as an APC component.\",\n      \"method\": \"Temperature-sensitive mutant analysis, in vivo co-immunoprecipitation, sucrose gradient sedimentation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP and sedimentation with multiple APC subunits, loss-of-function phenotype established\",\n      \"pmids\": [\"9348530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"In budding yeast, cell cycle progression of bub2 cells in the presence of nocodazole requires the Cdc26 APC subunit, placing CDC26 in a pathway distinct from the Mad2 checkpoint branch; Cdc26 is specifically required for Bub2-dependent (but not Mad2-dependent) mitotic arrest bypass.\",\n      \"method\": \"Genetic epistasis using double mutants (bub2 cdc26, mad2 cdc26) treated with nocodazole; DNA re-replication assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic epistasis in budding yeast, single lab but multiple mutant combinations tested\",\n      \"pmids\": [\"10352016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"In fission yeast, the Cdc26 orthologue Hcn1 can restore the assembly of the 20S APC/cyclosome when the cut9 mutant assembly is impaired, indicating a role in stabilizing or assembling the APC/C complex.\",\n      \"method\": \"Genetic suppression: elevated Hcn1 levels rescue cut9 mutant APC assembly defect; sucrose gradient analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue experiment with complex assembly readout, single lab\",\n      \"pmids\": [\"9264466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CDC26 was identified by mass spectrometry as a subunit of the human APC, confirming its conservation from yeast to vertebrates.\",\n      \"method\": \"Mass spectrometric identification of APC subunits from purified human APC\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry from purified human complex, single lab\",\n      \"pmids\": [\"10922056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CDC26 stabilizes the structure of APC6 (a core TPR subunit of the APC/C) through an intermolecular TPR mimic composed of one helix from each protein; CDC26-APC6 association is required for APC assembly.\",\n      \"method\": \"Biophysical analysis, crystal structure determination, genetic studies\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with biophysical and genetic validation, directly establishes molecular mechanism of CDC26-APC6 interaction\",\n      \"pmids\": [\"19668213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of S. pombe Cut9 (Cdc16/APC6) in complex with Hcn1 (Cdc26 orthologue) reveals that Cdc16/Cut9 is a contiguous TPR superhelix of 14 TPR units; the C-terminal TPR block interacts with Hcn1, and the acetylated N-terminal Met of Hcn1 is enclosed within a chamber in the Cut9 TPR superhelix, making the N-acetyl-Met degron inaccessible to the Doa10 E3 ubiquitin ligase and thereby protecting Hcn1/Cdc26 from ubiquitin-dependent degradation.\",\n      \"method\": \"Crystal structure determination of Cut9-Hcn1 complex\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structure providing mechanistic explanation for CDC26 stability and its interaction with APC6\",\n      \"pmids\": [\"20924356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LATS1 and LATS2 directly phosphorylate CDC26 at Thr7 (T7) in human cells; this phosphorylation reduces the interaction of CDC26 with APC6, alters APC/C assembly as measured by gel filtration, and a phosphomimetic T7D mutant of CDC26 promotes ubiquitination of polo-like kinase 1 (a known APC/C substrate).\",\n      \"method\": \"In vitro kinase assay (LATS1 phosphorylates CDC26 T7), siRNA knockdown of LATS1/LATS2 in HeLa cells, co-immunoprecipitation of CDC26 with APC6, gel filtration of APC/C subunits, ubiquitination assay with T7D mutant\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay, mutagenesis, co-IP, ubiquitination assay; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"25723520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Loss-of-function mutations in zebrafish cdc26 result in mitotic arrest followed by apoptosis in dividing cells, and improper re-entry into the cell cycle in quiescent/differentiated cells, demonstrating APC/C requirement in both dividing and non-dividing vertebrate cells.\",\n      \"method\": \"Zebrafish genetic mutant analysis; phenotypic characterization of cdc26 loss-of-function\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined loss-of-function phenotype in vertebrate model organism with two distinct cellular readouts, single lab\",\n      \"pmids\": [\"17141209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"C. elegans B0511.9 (CDC-26 orthologue) shares N-terminal sequence conservation with Cdc26 orthologues, and strong RNAi inhibition causes metaphase I arrest in meiosis, phenocopying APC/C mutants; B0511.9 functionally complements the temperature-sensitive growth defect of a yeast cdc26Δ mutant.\",\n      \"method\": \"RNAi phenotypic analysis in C. elegans embryos, functional complementation of yeast cdc26Δ\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cross-species functional rescue plus RNAi phenotype, two orthogonal methods, single lab\",\n      \"pmids\": [\"17374146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Arabidopsis, AtCDC26 (encoded by a uORF within the AtTTM3 transcript) is part of the plant APC/C, regulates accumulation of APC/C target proteins, and controls cell division, growth, and embryo development; AtTTM3 coordinates AtCDC26 translation by recruiting the transcript into polysomes.\",\n      \"method\": \"Loss-of-function mutant analysis, immunoprecipitation to show APC/C membership, western blotting for APC/C target protein levels, polysome profiling\",\n      \"journal\": \"Nature plants\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods including co-IP for APC/C membership and polysome analysis, single lab, plant ortholog\",\n      \"pmids\": [\"30737513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A homozygous missense mutation in APC12/CDC26 (p.R8H) disrupts the interaction between APC12 and APC6 and impairs APC/C-mediated Securin ubiquitination, causing meiotic metaphase I arrest in oocytes and female infertility; knockdown of APC12 in mouse oocytes and Apc12+/- mice recapitulate this arrest phenotype.\",\n      \"method\": \"Whole-exome sequencing, oocyte microinjection of mutant cRNA, co-immunoprecipitation (APC12–APC6 interaction), western blotting (Securin accumulation), siRNA knockdown in mouse oocytes, Apc12+/- mouse model, rescue by Apc12 cRNA injection\",\n      \"journal\": \"American journal of obstetrics and gynecology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (co-IP, ubiquitination assay, mouse KO model, rescue experiment) establishing mechanism of disease-causing mutation\",\n      \"pmids\": [\"39542389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDC26 protein levels are decreased in aged human and mouse oocytes, and loss of CDC26 is associated with increased aneuploidy during oocyte maturation; overexpression of CDC26 partially rescues oocyte aging defects including spindle and chromosomal abnormalities.\",\n      \"method\": \"Single-cell RNA-seq, immunocytochemistry, lentiviral overexpression in human oocytes, mouse oocyte in vitro maturation with CDC26 manipulation\",\n      \"journal\": \"Human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function and rescue experiments with defined phenotypic readouts (aneuploidy, maturation rates), single lab, lacks direct molecular mechanism beyond APC/C membership\",\n      \"pmids\": [\"34590680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDC26 overexpression in human pancreatic ductal adenocarcinoma cells promotes ferroptosis by enhancing ROS and lipid peroxidation; mechanistically, CDC26 promotes ubiquitin-mediated degradation of SLC7A11 (a key ferroptosis inhibitor) and indirectly inhibits the cell cycle, sensitizing cells to ferroptosis.\",\n      \"method\": \"CDC26 overexpression experiments, ROS and lipid peroxidation assays, ubiquitination assay for SLC7A11, cell proliferation and invasion assays\",\n      \"journal\": \"Clinical and experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — single lab, mechanistic claim for SLC7A11 ubiquitination based on overexpression and ubiquitination assay; functional phenotype established but molecular detail limited\",\n      \"pmids\": [\"41249642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The CDC26 gene in S. cerevisiae is required for cell growth only at high temperature; disruption of the gene confers thermosensitive growth, and the CDC26 gene is the same locus as SCD26 (a dosage-dependent suppressor of cdc26).\",\n      \"method\": \"Gene disruption, cloning and sequencing, complementation analysis, identification of nonsense mutation in cdc26-1\",\n      \"journal\": \"Molecular & general genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic analysis with gene disruption and sequencing, defining essential function at elevated temperature\",\n      \"pmids\": [\"1736102\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDC26 (APC12/ANAPC12) is a conserved small subunit of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase that stabilizes the TPR subunit APC6 through an intermolecular TPR-mimic interaction, is required for proper APC/C assembly, and is phosphorylated by LATS1/2 at Thr7 to modulate its interaction with APC6 and APC/C assembly state; loss of CDC26 impairs APC/C-mediated ubiquitination of substrates such as Securin and cyclin B, causing mitotic/meiotic arrest, and CDC26 also promotes ferroptosis in cancer cells by facilitating ubiquitin-mediated degradation of SLC7A11.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDC26 (APC12/ANAPC12) is a small, conserved subunit of the anaphase-promoting complex/cyclosome (APC/C), the cell cycle-regulated ubiquitin-protein ligase required for entry into anaphase and proteolysis of B-type cyclins [#0, #1, #4]. Within the complex it acts as a structural stabilizer of the core TPR subunit APC6 (Cdc16/Cut9): one helix from each protein forms an intermolecular TPR mimic that is required for proper APC/C assembly, and burial of CDC26's acetylated N-terminal methionine within the APC6 TPR superhelix shields an N-degron that would otherwise target CDC26 for degradation [#5, #6]. Loss of CDC26 prevents APC/C-mediated ubiquitination of substrates including mitotic cyclins, Securin, and Polo-like kinase 1, blocking cyclin proteolysis and producing mitotic or meiotic metaphase arrest across yeast, zebrafish, C. elegans, plant, and mammalian systems [#1, #7, #8, #9, #10, #11]. CDC26 activity is regulated by LATS1/2, which directly phosphorylate it at Thr7 to weaken the APC6 interaction and reshape APC/C assembly [#7]. In human oocytes, a homozygous APC12/CDC26 p.R8H mutation disrupts the APC12-APC6 interaction and impairs Securin ubiquitination, causing meiotic metaphase I arrest and female infertility [#11]. Beyond its APC/C role, CDC26 promotes ferroptosis in pancreatic cancer cells by facilitating ubiquitin-mediated degradation of the ferroptosis inhibitor SLC7A11 [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established CDC26 as a genetically defined locus whose product is required for cell growth specifically at elevated temperature, the first functional handle on the gene.\",\n      \"evidence\": \"Gene disruption, cloning, sequencing, and complementation in S. cerevisiae\",\n      \"pmids\": [\"1736102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular function or biochemical role identified\", \"Temperature-dependent essentiality mechanism unexplained\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Placed CDC26 inside the APC/cyclosome by identifying it as a subunit of the purified ubiquitin-ligase particle, defining its molecular context.\",\n      \"evidence\": \"Biochemical purification and subunit identification of the yeast APC complex\",\n      \"pmids\": [\"8895471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural role within the complex not defined\", \"Substrate specificity contribution unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Confirmed CDC26 as an integral APC component and linked its loss to a failure of mitotic cyclin proteolysis, connecting the subunit to ubiquitin-dependent cell cycle control.\",\n      \"evidence\": \"Temperature-sensitive mutant analysis, in vivo co-IP with Doc1/Cdc16/Cdc23/Cdc27, and sucrose gradient sedimentation in budding yeast\",\n      \"pmids\": [\"9348530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct contribution to catalysis vs assembly not separated\", \"Which subunit CDC26 contacts not resolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed CDC26 functions in APC/C assembly by demonstrating its fission yeast orthologue restores 20S complex assembly in a cut9 (APC6) mutant, foreshadowing the CDC26-APC6 relationship.\",\n      \"evidence\": \"Genetic suppression and sucrose gradient analysis of Hcn1 rescue of cut9 in S. pombe\",\n      \"pmids\": [\"9264466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of assembly stabilization unknown\", \"Single-lab genetic readout\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined CDC26's checkpoint context, showing it is required for Bub2-dependent but not Mad2-dependent mitotic arrest bypass, separating its pathway from the spindle assembly checkpoint branch.\",\n      \"evidence\": \"Genetic epistasis with double mutants and DNA re-replication assays in budding yeast\",\n      \"pmids\": [\"10352016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between CDC26/APC and Bub2 not defined\", \"Restricted to budding yeast\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated conservation of CDC26 as an APC subunit in humans, extending its function from yeast to vertebrates.\",\n      \"evidence\": \"Mass spectrometric identification of subunits from purified human APC\",\n      \"pmids\": [\"10922056\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Human-specific functional role not tested\", \"Regulation in human cells unaddressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the vertebrate requirement for CDC26 in both proliferating and quiescent cells, showing loss causes mitotic arrest with apoptosis and aberrant cell cycle re-entry.\",\n      \"evidence\": \"Zebrafish cdc26 loss-of-function mutant phenotyping\",\n      \"pmids\": [\"17141209\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular substrate-level mechanism not addressed\", \"Cause of aberrant re-entry in differentiated cells unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Confirmed functional conservation across metazoa by showing the C. elegans orthologue causes meiotic metaphase I arrest on depletion and complements a yeast cdc26 deletion.\",\n      \"evidence\": \"RNAi phenotyping in C. elegans embryos and cross-species yeast complementation\",\n      \"pmids\": [\"17374146\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Meiotic substrate specificity not defined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved CDC26's structural role: it stabilizes APC6 via an intermolecular TPR mimic in which each protein contributes one helix, an interaction required for complex assembly.\",\n      \"evidence\": \"Crystal structure, biophysics, and genetic studies of CDC26-APC6\",\n      \"pmids\": [\"19668213\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CDC26 contributes beyond APC6 stabilization unresolved\", \"Regulation of the interaction not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Explained CDC26 protein stability by showing its acetylated N-terminal methionine is sequestered within the APC6 TPR superhelix, shielding an N-degron from the Doa10 E3 ligase.\",\n      \"evidence\": \"Crystal structure of S. pombe Cut9-Hcn1 complex\",\n      \"pmids\": [\"20924356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether degron shielding operates identically in humans not tested\", \"Turnover dynamics of free vs assembled CDC26 unmeasured\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a regulatory input on CDC26: LATS1/2 directly phosphorylate Thr7 to weaken the APC6 interaction and alter APC/C assembly, modulating substrate ubiquitination.\",\n      \"evidence\": \"In vitro kinase assay, LATS1/2 knockdown, co-IP, gel filtration, and PLK1 ubiquitination assay with a T7D phosphomimetic in human cells\",\n      \"pmids\": [\"25723520\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular contexts where this phosphorylation operates not mapped\", \"Quantitative effect on global APC/C output unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended CDC26 function to plants and revealed translational control, showing AtCDC26 is encoded by a uORF whose translation is coordinated by AtTTM3 and is required for APC/C function in development.\",\n      \"evidence\": \"Loss-of-function mutants, co-IP for APC/C membership, target protein westerns, and polysome profiling in Arabidopsis\",\n      \"pmids\": [\"30737513\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether uORF-based regulation occurs outside plants unknown\", \"Mechanism of TTM3-mediated polysome recruitment not detailed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked CDC26 to oocyte aging, showing declining CDC26 correlates with aneuploidy and that overexpression partially rescues spindle and chromosomal defects.\",\n      \"evidence\": \"Single-cell RNA-seq, immunocytochemistry, and lentiviral CDC26 manipulation in human and mouse oocytes\",\n      \"pmids\": [\"34590680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular mechanism beyond APC/C membership not established\", \"Cause of age-related CDC26 decline unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established CDC26 as a human disease gene, showing a homozygous p.R8H mutation disrupts APC12-APC6 binding and Securin ubiquitination, causing meiotic arrest and female infertility.\",\n      \"evidence\": \"Whole-exome sequencing, oocyte cRNA microinjection, co-IP, Securin westerns, mouse knockdown and Apc12+/- model with cRNA rescue\",\n      \"pmids\": [\"39542389\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Penetrance and broader phenotypic spectrum in patients not defined\", \"Whether other APC/C substrates are affected not fully mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered a cancer-relevant CDC26 function, showing it promotes ferroptosis in pancreatic cancer cells by facilitating ubiquitin-mediated degradation of SLC7A11.\",\n      \"evidence\": \"CDC26 overexpression, ROS and lipid peroxidation assays, and SLC7A11 ubiquitination assay in PDAC cells\",\n      \"pmids\": [\"41249642\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SLC7A11 degradation is APC/C-dependent not established\", \"Single-lab, overexpression-based mechanism without loss-of-function validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CDC26 regulation (e.g. LATS-dependent phosphorylation) and its newly described ferroptosis/SLC7A11 role integrate with canonical APC/C cell cycle function across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstitution linking SLC7A11 degradation to APC/C activity\", \"Tissue-specific physiological consequences of CDC26 regulation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 11, 13]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 5, 7]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 8, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 7, 11]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\"APC/C (anaphase-promoting complex/cyclosome)\"],\n    \"partners\": [\"APC6\", \"CDC16\", \"CDC23\", \"CDC27\", \"DOC1\", \"LATS1\", \"LATS2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}