{"gene":"CDC27","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1995,"finding":"CDC27 (APC3) is a core subunit of the 20S anaphase-promoting complex (APC), which functions as a regulated ubiquitin-protein ligase that catalyzes mitosis-specific ubiquitin conjugation to cyclin B, targeting it for proteasomal destruction. CDC27 antibody depletion abolishes APC ubiquitin-ligase activity, while immunopurified CDC27 complexes reconstitute cyclin B ubiquitination in vitro.","method":"Biochemical fractionation of Xenopus mitotic egg extracts, immunodepletion with CDC27 antibodies, immunopurification, in vitro ubiquitination reconstitution assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of ubiquitin ligase activity, immunodepletion, and complementation assays; foundational paper replicated across many subsequent studies","pmids":["7736580"],"is_preprint":false},{"year":1988,"finding":"The S. pombe nuc2+ gene (ortholog of CDC27) encodes a nuclear scaffold-associated protein required for mitotic spindle elongation; its temperature-sensitive mutation arrests cells at a metaphase-like stage with a short spindle, and the protein co-fractionates with nuclei and insoluble nuclear scaffold.","method":"Temperature-sensitive mutant analysis, cellular fractionation, immunoblotting, Percoll gradient centrifugation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined phenotypic readout plus biochemical fractionation; replicated in multiple subsequent fission yeast studies","pmids":["3283148"],"is_preprint":false},{"year":1990,"finding":"The nuc2+ protein (S. pombe CDC27 ortholog) contains ten 34-amino acid tetratricopeptide repeat (TPR) segments forming a 'snap helix' secondary structure with knob-and-hole helix-associating motifs, and also contains a domain capable of binding AT-rich DNA in vitro.","method":"Circular dichroism, limited proteolysis, model fitting, in vitro DNA-binding assay","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — biophysical characterization of protein structure with in vitro functional assay, single lab","pmids":["2297790"],"is_preprint":false},{"year":1997,"finding":"The serine/threonine phosphatase PP5 physically interacts with CDC16 and CDC27, two TPR-containing APC/C subunits, via the N-terminal TPR domain of PP5; the binding site on CDC16 and CDC27 maps to their C-terminal TPR block. PP5 co-localizes with the mitotic spindle apparatus by indirect immunofluorescence.","method":"Yeast two-hybrid, in vitro binding assay, deletion analysis, indirect immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus in vitro binding (two orthogonal methods), single lab","pmids":["9405394"],"is_preprint":false},{"year":1998,"finding":"In budding yeast, CDC27 (together with CDC23) is required for the proteolytic instability of the APC/C coactivator Cdc20 during S phase and early mitosis; this degradation is independent of Cdc20's canonical destruction box, revealing a destruction-box-independent APC/C-mediated degradation pathway.","method":"Yeast genetics, cell cycle synchronization, protein stability assays, CDC27 and CDC23 mutant analysis","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with biochemical protein stability readout, single lab but multiple alleles tested","pmids":["9651679"],"is_preprint":false},{"year":1996,"finding":"In S. cerevisiae, CDC16 and CDC27 restrict DNA replication to once per cell cycle; conditional alleles of these genes cause accumulation of up to 8C DNA content without passage through mitosis, implicating APC/C-mediated proteolysis of an S-phase initiator in replication licensing control.","method":"Genetic screen, flow cytometry, conditional (ts) allele analysis","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined molecular phenotype (DNA overreplication), single lab","pmids":["8620535"],"is_preprint":false},{"year":2002,"finding":"The dephosphorylated form of human Cdc27/APC3 specifically associates with kinetochores and chromosome arms during mitosis (in addition to spindle poles and microtubules); only dephosphorylated Cdc27 is found on isolated chromosomes, and chromosome-associated kinases phosphorylate Cdc27 in vitro. Microinjection of anti-Cdc27 antibody arrests cells in metaphase and overrides premature anaphase induced by anti-Mad2 antibody.","method":"Immunofluorescence, chromosome isolation/fractionation, in vitro phosphorylation assay, antibody microinjection","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (fractionation, microinjection, phosphorylation assay), single lab","pmids":["12429948"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of the N-terminal domain of Encephalitozoon cuniculi Cdc27 reveals a homo-dimeric TPR superhelix; mutation of the dimer interface destabilizes the protein, disrupts dimerization in solution, and abolishes complementation of S. cerevisiae cdc27 deletion in vivo, establishing that homo-dimerization via TPR motifs is evolutionarily conserved and functionally essential.","method":"X-ray crystallography, solution biophysics, site-directed mutagenesis, in vivo complementation assay","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus in vivo complementation in a single rigorous study","pmids":["20206185"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of S. pombe Cdc16/Cut9 (APC6) in complex with Hcn1 (Cdc26) shows Cdc16 forms a contiguous 14-TPR superhelix; its N-terminal TPR block mediates homo-dimerization through an interface structurally related to the Cdc27 dimerization domain, demonstrating both APC/C TPR subunits use a conserved homo-dimerization mechanism. The N-acetyl-Met of Hcn1 is enclosed within the Cut9 superhelix, protecting it from Doa10 ubiquitin ligase recognition.","method":"X-ray crystallography","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with direct structural comparison to Cdc27, mechanistic interpretation validated by structure","pmids":["20924356"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of human APC3 (CDC27) alone and in complex with the C-terminal domain of APC16 reveals: (1) one APC16 binds asymmetrically to the symmetric APC3 dimer; (2) APC3's C-terminal IR-tail binding cleft is critical for coactivator (CDC20/CDH1) recruitment and APC/C-catalyzed ubiquitination; (3) APC16 recruits APC7 to APC3; (4) APC3's >200-residue phosphorylation loop is not required for ubiquitination in vitro.","method":"X-ray crystallography, biochemical ubiquitination assay, deletion/mutation analysis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro ubiquitination assays with mutagenesis, multiple mechanistic findings in one study","pmids":["25490258"],"is_preprint":false},{"year":2004,"finding":"Swm1/Apc13 stabilizes the association of Cdc16 and Cdc27 within the APC/C; deletion of SWM1 reduces the stable incorporation of these subunits into the complex and abolishes APC/C ubiquitin-ligase activity in vitro.","method":"Yeast genetics, co-immunoprecipitation, in vitro ubiquitination assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic deletion with biochemical readout (Co-IP and in vitro ligase assay), single lab","pmids":["15060174"],"is_preprint":false},{"year":2011,"finding":"Microcephalin (MCPH1) C-terminal tandem BRCT domains bind CDC27 in a phosphorylation-dependent manner; crystal structure of MCPH1 C-BRCTs in complex with a phosphorylated CDC27 peptide defines the binding interface, and single amino acid mutations at this interface disrupt the interaction in vitro and in vivo.","method":"Co-immunoprecipitation, in vitro binding assay, X-ray crystallography, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus orthogonal Co-IP/in vitro binding, multiple methods in one study","pmids":["22139841"],"is_preprint":false},{"year":2011,"finding":"Phosphorylation of CDC27 by casein kinase II (CKII) in response to TGF-β signaling facilitates APC/C activation and subsequent SnoN degradation; shRNA depletion of CKII abolishes TGF-β-induced CDC27 phosphorylation and SnoN destruction, and a phosphorylation-resistant CDC27 S154A mutant attenuates TGF-β-induced growth inhibition.","method":"shRNA knockdown, site-directed mutagenesis (S154A), phosphorylation assay, co-immunoprecipitation, ubiquitination assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic/pharmacological perturbation plus phospho-mutant functional analysis, single lab, multiple methods","pmids":["21209074"],"is_preprint":false},{"year":2010,"finding":"C/EBPδ transcriptionally induces CDC27 (APC3) expression, which leads to APC/C-Cdh1-mediated polyubiquitination and proteasomal degradation of cyclin D1 (as well as cyclin B1, Skp2, and Plk-1); C/EBPδ-knockout MEFs have reduced Cdc27 and elevated cyclin D1, and silencing of CDC27 or Cdh1 in breast epithelial cells increases cyclin D1 protein levels.","method":"siRNA knockdown, C/EBPδ knockout MEFs, Western blotting, co-immunoprecipitation, ubiquitination assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus RNAi with biochemical ubiquitination readout, single lab, multiple orthogonal approaches","pmids":["20439707"],"is_preprint":false},{"year":2016,"finding":"The RNA-binding protein HNRNP E1 (PCBP1) post-transcriptionally silences CDC27 translation in normal mammary epithelial cells; shRNA-mediated knockdown of HNRNP E1 leads to constitutive CDC27 expression, premature activation of the G2-M APC/C-CDC20 complex, aberrant degradation of CDH1/FZR1, and consequent mitotic aberrations and aneuploidy.","method":"shRNA knockdown, Western blotting, cell cycle analysis, aneuploidy scoring, co-immunoprecipitation","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular and cellular phenotype, single lab, multiple methods","pmids":["27102006"],"is_preprint":false},{"year":2003,"finding":"The Drosophila mákos (mks) gene encodes the Cdc27 subunit of APC/C; mks mutant neuroblasts arrest in a metaphase-like state with elevated cyclin A and cyclin B. Loss of mks enhances centrosomal defects in polo hypomorphs (reduced γ-tubulin and CP190 at spindle poles). The metaphase arrest of mks mutants is not suppressed by bub1 spindle checkpoint mutations (confirming the checkpoint must act through APC/C), but is suppressed by mutations in twins/aar (PP2A regulatory subunit B55), indicating PP2A acts downstream of APC/C to initiate anaphase.","method":"Drosophila genetics, epistasis analysis (double mutants), immunofluorescence, immunohistochemistry","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple double mutant combinations and clear functional readouts, single lab","pmids":["12953067"],"is_preprint":false},{"year":2007,"finding":"Two Cdk1 phosphorylation consensus sites on Drosophila Cdc27 (at P304 and P456) are jointly required for chromosomal localization of GFP::Cdc27 during mitosis and for APC/C function in vivo; the double proline-to-alanine mutant (P304A,P456A) fails to localize to mitotic chromosomes and cannot rescue cdc27 mutant phenotypes, while single mutants remain functional.","method":"Site-directed mutagenesis, GFP live imaging in Drosophila syncytial embryos, in vivo rescue assay, immunostaining for cyclin B and A","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with in vivo functional rescue and live imaging, single lab","pmids":["17519285"],"is_preprint":false},{"year":2012,"finding":"Curcumin directly binds to and crosslinks CDC27/APC3, inhibiting APC/C ubiquitin ligase activity; cells with phosphorylated CDC27 (found in highly proliferating cells) are preferentially driven to apoptosis by curcumin treatment.","method":"Pull-down assay (curcumin-bead binding), in vitro APC/C ubiquitination assay, cell cycle profiling","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by pulldown plus in vitro activity assay, single lab","pmids":["22280307"],"is_preprint":false},{"year":2005,"finding":"In Trypanosoma brucei, depletion of CDC27 by RNAi arrests procyclic-form cells in metaphase (two kinetoplasts, short metaphase-like spindle) and bloodstream-form cells in late anaphase, demonstrating an essential role of CDC27/APC/C in promoting anaphase in both life-cycle stages.","method":"RNA interference, FACS cell cycle analysis, fluorescence microscopy","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with defined mitotic phenotypes in two cell types, single lab","pmids":["15994309"],"is_preprint":false},{"year":2016,"finding":"CDC27 knockdown in colorectal cancer cells causes G1/S arrest through accumulation of p21 (Cip1/Waf1), mediated via downregulation of ID1; CDC27 overexpression reduces p21 and promotes G1/S progression through ID1-dependent p21 suppression.","method":"shRNA knockdown, CDC27 overexpression, cell cycle analysis, Western blotting, rescue assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with pathway rescue experiments, single lab","pmids":["26821069"],"is_preprint":false},{"year":2023,"finding":"In cisplatin-treated human cancer cells, Mad2B (Mad2L2) exists in a basal complex with APC/C subunit CDC27, DNA polymerase ζ (Rev3/Rev1); upon cisplatin-induced DNA damage, CDC20 is additionally recruited to this complex and APC/C ubiquitination activity is enhanced in a Mad2B-dependent manner.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, fluorescence microscopy (focus recruitment)","journal":"The Korean journal of physiology & pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus in vitro ubiquitination assay, single lab","pmids":["37641805"],"is_preprint":false},{"year":2025,"finding":"CDC27 is O-GlcNAcylated by OGT (O-GlcNAc transferase) in multiple myeloma cells; O-GlcNAcylation stabilizes CDC27 protein by blocking its degradation through the autophagy-lysosome pathway. Pharmacological inhibition of O-GlcNAcylation (OSMI-1) reduces CDC27 protein levels identified by mass spectrometry and immunoprecipitation.","method":"Mass spectrometry, immunoprecipitation, siRNA knockdown of OGT, pharmacological inhibition/accumulation of O-GlcNAcylation, Western blotting","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry identification of modification plus pharmacological and genetic perturbation, single lab","pmids":["39984622"],"is_preprint":false},{"year":1995,"finding":"Human CDC27 (H-NUC) is a nuclear protein that binds to hypophosphorylated retinoblastoma protein (Rb) via two distinct regions: one overlapping the binding motif for SV40 large T antigen, and a second involving CDC27's TPR motifs. A temperature-sensitive point mutant (G640D) of CDC27 loses Rb binding at restrictive temperature.","method":"Co-immunoprecipitation, in vitro binding assay, temperature-sensitive mutagenesis, subcellular fractionation, DNA-binding assay","journal":"Cell growth & differentiation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus in vitro binding and mutagenesis but single lab and functional significance not fully defined","pmids":["7756179"],"is_preprint":false},{"year":2016,"finding":"Cdc27 interacts with Elmo1 at the C-terminal region of Elmo1 that is essential for Dock1 association; the Elmo1-Dock1 interaction abrogates Elmo1-Cdc27 binding, but Cdc27 levels do not affect Dock1-Elmo1 interaction or Elmo1-Dock1-Rac-mediated phagocytosis.","method":"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, domain mapping","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with domain mapping, single lab, limited functional follow-up","pmids":["26882976"],"is_preprint":false},{"year":2022,"finding":"Nuclear-localized CTEN associates with the CDC27 gene promoter and transcriptionally activates CDC27 expression; CTEN overexpression with nuclear localization signals increases CDC27 mRNA and promoter activity, and CDC27 knockdown suppresses the CTEN-mediated increase in cell migration.","method":"ChIP assay, luciferase reporter assay, shRNA knockdown, RT-qPCR, migration assay","journal":"Journal of physiology and biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP and reporter assay for transcriptional regulation, single lab, limited mechanistic depth","pmids":["36399312"],"is_preprint":false},{"year":2024,"finding":"cdc27 knockout in zebrafish causes craniofacial malformation, spine deformity, and cardiac edema mirroring hemifacial microsomia phenotypes; mechanistically, loss of cdc27 reduces neural crest cell (NCC) proliferation in pharyngeal arches and disrupts chondrocyte differentiation. Rescue by cdc27 mRNA injection or cdkn1a/tp53 knockout (but only partial rescue by sox9a mRNA) places cdc27 upstream of the p21/p53 pathway in pharyngeal arch development.","method":"CRISPR/Cas9 knockout in zebrafish, in situ hybridization, immunofluorescence (PH3), TUNEL assay, RNA sequencing, mRNA injection rescue, genetic epistasis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple orthogonal assays and epistasis rescue experiments, single lab","pmids":["38731925"],"is_preprint":false},{"year":2024,"finding":"SIX1 promotes nasopharyngeal carcinoma progression through the CDC27/cyclin B1 axis; SIX1 knockdown reduces CDC27 and cyclin B1 levels, and SIX1 overexpression increases them. The E3 ligase ITCH ubiquitinates SIX1 to promote its degradation, thereby suppressing CDC27-cyclin B1-driven tumor phenotypes.","method":"siRNA knockdown, Western blotting, co-immunoprecipitation, cell proliferation/migration/invasion assays","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single-lab knockdown/overexpression study with Western blot readout; indirect pathway placement for CDC27","pmids":["39406717"],"is_preprint":false}],"current_model":"CDC27/APC3 is a core TPR-repeat subunit of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase that homo-dimerizes through a conserved TPR superhelix and serves as a structural hub recruiting coactivators (CDC20, CDH1) via its C-terminal IR-tail binding cleft; in mitosis, Cdk1-mediated phosphorylation of CDC27 directs its chromosomal localization and is required for full APC/C activity, while casein kinase II-mediated phosphorylation links TGF-β signaling to APC/C activation, O-GlcNAcylation by OGT stabilizes CDC27 protein by blocking autophagy-lysosomal degradation, and the APC/C-CDC27 complex catalyzes ubiquitination of cyclin B, securin, cyclin A, and other cell cycle regulators to drive the metaphase-to-anaphase transition and mitotic exit."},"narrative":{"mechanistic_narrative":"CDC27 (APC3) is a core, structurally essential subunit of the anaphase-promoting complex/cyclosome (APC/C), a regulated ubiquitin-protein ligase that catalyzes mitosis-specific polyubiquitination of cyclin B and other cell cycle regulators to drive the metaphase-to-anaphase transition [PMID:7736580]. Genetic loss of CDC27 orthologs arrests cells at a metaphase-like stage with elevated cyclins A and B across fission yeast, Drosophila, and trypanosomes, confirming its conserved and essential role in promoting anaphase [PMID:3283148, PMID:12953067, PMID:15994309]. CDC27 is built from tandem tetratricopeptide (TPR) repeats that form a superhelix [PMID:2297790], and crystallographic work establishes that this TPR domain mediates an evolutionarily conserved, functionally essential homo-dimerization shared with the related APC/C subunit Cdc16/APC6 [PMID:20206185, PMID:20924356]. Within the assembled complex CDC27 serves as a structural hub: its C-terminal IR-tail binding cleft recruits the coactivators CDC20 and CDH1 and is required for APC/C-catalyzed ubiquitination, while APC16 binds asymmetrically to the symmetric CDC27 dimer and bridges APC7 into the complex [PMID:25490258]; stable incorporation of CDC27 itself depends on the accessory subunit Swm1/Apc13 [PMID:15060174]. CDC27 activity and abundance are governed by multiple post-translational and regulatory inputs: Cdk1 phosphorylation at consensus sites directs its chromosomal localization and is required for full APC/C function [PMID:17519285], dephosphorylated CDC27 specifically associates with kinetochores and chromosome arms during mitosis [PMID:12429948], casein kinase II phosphorylation links TGF-β signaling to APC/C-driven SnoN degradation [PMID:21209074], and O-GlcNAcylation by OGT stabilizes CDC27 by blocking autophagy-lysosomal degradation [PMID:39984622]. Through APC/C-CDH1 it directs degradation of cyclin D1, cyclin B1, Skp2 and Plk-1 [PMID:20439707], and its expression and translation are controlled transcriptionally by C/EBPδ [PMID:20439707] and post-transcriptionally by HNRNP E1, whose loss causes premature APC/C activation and aneuploidy [PMID:27102006]. Zebrafish cdc27 knockout produces craniofacial and skeletal malformations resembling hemifacial microsomia via reduced neural crest proliferation acting upstream of the p21/p53 pathway [PMID:38731925].","teleology":[{"year":1988,"claim":"Established that the CDC27 ortholog is an essential nuclear factor required for mitotic spindle elongation, the first link of the gene to anaphase progression.","evidence":"Temperature-sensitive mutant analysis and nuclear fractionation of S. pombe nuc2+","pmids":["3283148"],"confidence":"High","gaps":["Molecular activity unknown at this stage","No connection yet to ubiquitination or a defined complex"]},{"year":1990,"claim":"Defined the architecture of CDC27 as a TPR-repeat superhelix, identifying the structural module that would later mediate complex assembly and dimerization.","evidence":"Circular dichroism, limited proteolysis and in vitro DNA-binding of S. pombe nuc2+ protein","pmids":["2297790"],"confidence":"Medium","gaps":["Functional role of TPR repeats not yet established","In vitro AT-rich DNA binding of uncertain physiological relevance"]},{"year":1995,"claim":"Answered what CDC27 does biochemically by showing it is a subunit of the 20S APC ubiquitin ligase required for cyclin B ubiquitination, defining its core enzymatic context.","evidence":"Immunodepletion and immunopurification from Xenopus mitotic extracts with in vitro ubiquitination reconstitution","pmids":["7736580"],"confidence":"High","gaps":["Did not define CDC27's specific role within the complex","Substrate range beyond cyclin B not addressed"]},{"year":1996,"claim":"Extended CDC27 function beyond mitotic exit, showing it restricts DNA replication to once per cycle via APC/C-mediated proteolysis.","evidence":"Genetic screen and flow cytometry of S. cerevisiae conditional alleles","pmids":["8620535"],"confidence":"Medium","gaps":["S-phase initiator substrate not identified","Mechanism inferred from DNA overreplication phenotype"]},{"year":1998,"claim":"Revealed a destruction-box-independent APC/C degradation route by which CDC27 controls coactivator Cdc20 stability, expanding regulatory logic of the complex.","evidence":"Yeast genetics and protein stability assays with CDC27/CDC23 mutants","pmids":["9651679"],"confidence":"Medium","gaps":["Degron and recruitment mechanism undefined","Single-organism evidence"]},{"year":2002,"claim":"Linked CDC27 phosphorylation state to spatial regulation, showing dephosphorylated CDC27 associates with kinetochores and chromosomes and is required to maintain metaphase.","evidence":"Immunofluorescence, chromosome fractionation, in vitro phosphorylation and antibody microinjection in human cells","pmids":["12429948"],"confidence":"Medium","gaps":["Responsible kinases/phosphatases not fully defined","Functional consequence of chromosomal pool unclear"]},{"year":2007,"claim":"Identified Cdk1 phosphorylation sites required for CDC27 chromosomal localization and APC/C function in vivo, connecting mitotic kinase activity to CDC27 targeting.","evidence":"Site-directed mutagenesis, GFP live imaging and rescue in Drosophila embryos","pmids":["17519285"],"confidence":"Medium","gaps":["Whether human CDC27 uses identical sites not addressed here","Link between localization and catalytic activity correlative"]},{"year":2010,"claim":"Resolved the structural basis of CDC27 function, showing TPR-mediated homo-dimerization is conserved and essential and is shared with the APC6 subunit.","evidence":"X-ray crystallography of E. cuniculi Cdc27 and S. pombe Cdc16, with mutagenesis and in vivo complementation","pmids":["20206185","20924356"],"confidence":"High","gaps":["Did not resolve coactivator-binding interface","Human complex architecture inferred from fungal/microsporidian structures"]},{"year":2014,"claim":"Defined CDC27 as the coactivator-recruiting hub by mapping its IR-tail binding cleft and its asymmetric engagement of APC16/APC7, explaining how it scaffolds the active ligase.","evidence":"Crystallography of human APC3 alone and with APC16, plus in vitro ubiquitination assays","pmids":["25490258"],"confidence":"High","gaps":["Phosphorylation loop function in vivo not resolved (dispensable in vitro)","Dynamics of coactivator exchange not addressed"]},{"year":2011,"claim":"Established phosphorylation-dependent and signaling-coupled regulation of CDC27 through MCPH1 BRCT binding and CKII-mediated TGF-β linkage to APC/C activation.","evidence":"Crystallography/Co-IP of MCPH1–CDC27 and shRNA/phospho-mutant analysis of CKII–TGF-β–SnoN axis","pmids":["22139841","21209074"],"confidence":"High","gaps":["Cellular consequence of MCPH1–CDC27 binding not fully defined","CKII regulation single-lab"]},{"year":2016,"claim":"Placed CDC27 under transcriptional and translational control coupled to cell cycle fidelity, showing C/EBPδ induction and HNRNP E1 silencing govern its level to prevent aneuploidy.","evidence":"siRNA/KO, shRNA, ubiquitination and cell cycle/aneuploidy assays in mammalian cells","pmids":["20439707","27102006"],"confidence":"Medium","gaps":["Causal chain to specific substrates partly correlative","Single-lab observations"]},{"year":2021,"claim":"Identified O-GlcNAcylation by OGT as a stabilizing modification that protects CDC27 from autophagy-lysosomal degradation, adding a metabolic input to CDC27 abundance.","evidence":"Mass spectrometry, IP, OGT siRNA and OSMI-1 inhibition in multiple myeloma cells","pmids":["39984622"],"confidence":"Medium","gaps":["GlcNAcylation sites not mapped","Single cell-type context"]},{"year":2024,"claim":"Defined a developmental requirement for CDC27, showing its loss causes craniofacial/skeletal malformation through reduced neural crest proliferation acting upstream of p21/p53.","evidence":"CRISPR knockout, in situ hybridization, PH3/TUNEL, RNA-seq and epistasis rescue in zebrafish","pmids":["38731925"],"confidence":"Medium","gaps":["Whether phenotype reflects APC/C ubiquitination activity not directly tested","Causal substrate linking CDC27 to p21/p53 not identified"]},{"year":null,"claim":"How the diverse regulatory inputs to CDC27 (Cdk1, CKII, O-GlcNAc, transcriptional/translational control) are integrated to tune APC/C activity in specific physiological and disease contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified quantitative model of CDC27 regulation","Mendelian disease causation in humans not established in this corpus","Substrate selectivity contributions of CDC27 versus coactivators incompletely defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,9,13]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[9]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[7,8,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,22]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[6,16]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,13,15]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,9]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[25]}],"complexes":["APC/C (anaphase-promoting complex/cyclosome)"],"partners":["CDC16","APC16","CDC20","CDH1/FZR1","MCPH1","PP5","MAD2L2","RB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P30260","full_name":"Cell division cycle protein 27 homolog","aliases":["Anaphase-promoting complex subunit 3","APC3","CDC27 homolog","CDC27Hs","H-NUC"],"length_aa":824,"mass_kda":91.9,"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":"Nucleus; Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/P30260/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CDC27","classification":"Common 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{\n      \"year\": 1995,\n      \"finding\": \"CDC27 (APC3) is a core subunit of the 20S anaphase-promoting complex (APC), which functions as a regulated ubiquitin-protein ligase that catalyzes mitosis-specific ubiquitin conjugation to cyclin B, targeting it for proteasomal destruction. CDC27 antibody depletion abolishes APC ubiquitin-ligase activity, while immunopurified CDC27 complexes reconstitute cyclin B ubiquitination in vitro.\",\n      \"method\": \"Biochemical fractionation of Xenopus mitotic egg extracts, immunodepletion with CDC27 antibodies, immunopurification, in vitro ubiquitination reconstitution assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of ubiquitin ligase activity, immunodepletion, and complementation assays; foundational paper replicated across many subsequent studies\",\n      \"pmids\": [\"7736580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"The S. pombe nuc2+ gene (ortholog of CDC27) encodes a nuclear scaffold-associated protein required for mitotic spindle elongation; its temperature-sensitive mutation arrests cells at a metaphase-like stage with a short spindle, and the protein co-fractionates with nuclei and insoluble nuclear scaffold.\",\n      \"method\": \"Temperature-sensitive mutant analysis, cellular fractionation, immunoblotting, Percoll gradient centrifugation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined phenotypic readout plus biochemical fractionation; replicated in multiple subsequent fission yeast studies\",\n      \"pmids\": [\"3283148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The nuc2+ protein (S. pombe CDC27 ortholog) contains ten 34-amino acid tetratricopeptide repeat (TPR) segments forming a 'snap helix' secondary structure with knob-and-hole helix-associating motifs, and also contains a domain capable of binding AT-rich DNA in vitro.\",\n      \"method\": \"Circular dichroism, limited proteolysis, model fitting, in vitro DNA-binding assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biophysical characterization of protein structure with in vitro functional assay, single lab\",\n      \"pmids\": [\"2297790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The serine/threonine phosphatase PP5 physically interacts with CDC16 and CDC27, two TPR-containing APC/C subunits, via the N-terminal TPR domain of PP5; the binding site on CDC16 and CDC27 maps to their C-terminal TPR block. PP5 co-localizes with the mitotic spindle apparatus by indirect immunofluorescence.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, deletion analysis, indirect immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus in vitro binding (two orthogonal methods), single lab\",\n      \"pmids\": [\"9405394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"In budding yeast, CDC27 (together with CDC23) is required for the proteolytic instability of the APC/C coactivator Cdc20 during S phase and early mitosis; this degradation is independent of Cdc20's canonical destruction box, revealing a destruction-box-independent APC/C-mediated degradation pathway.\",\n      \"method\": \"Yeast genetics, cell cycle synchronization, protein stability assays, CDC27 and CDC23 mutant analysis\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with biochemical protein stability readout, single lab but multiple alleles tested\",\n      \"pmids\": [\"9651679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"In S. cerevisiae, CDC16 and CDC27 restrict DNA replication to once per cell cycle; conditional alleles of these genes cause accumulation of up to 8C DNA content without passage through mitosis, implicating APC/C-mediated proteolysis of an S-phase initiator in replication licensing control.\",\n      \"method\": \"Genetic screen, flow cytometry, conditional (ts) allele analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined molecular phenotype (DNA overreplication), single lab\",\n      \"pmids\": [\"8620535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The dephosphorylated form of human Cdc27/APC3 specifically associates with kinetochores and chromosome arms during mitosis (in addition to spindle poles and microtubules); only dephosphorylated Cdc27 is found on isolated chromosomes, and chromosome-associated kinases phosphorylate Cdc27 in vitro. Microinjection of anti-Cdc27 antibody arrests cells in metaphase and overrides premature anaphase induced by anti-Mad2 antibody.\",\n      \"method\": \"Immunofluorescence, chromosome isolation/fractionation, in vitro phosphorylation assay, antibody microinjection\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (fractionation, microinjection, phosphorylation assay), single lab\",\n      \"pmids\": [\"12429948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of the N-terminal domain of Encephalitozoon cuniculi Cdc27 reveals a homo-dimeric TPR superhelix; mutation of the dimer interface destabilizes the protein, disrupts dimerization in solution, and abolishes complementation of S. cerevisiae cdc27 deletion in vivo, establishing that homo-dimerization via TPR motifs is evolutionarily conserved and functionally essential.\",\n      \"method\": \"X-ray crystallography, solution biophysics, site-directed mutagenesis, in vivo complementation assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus in vivo complementation in a single rigorous study\",\n      \"pmids\": [\"20206185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of S. pombe Cdc16/Cut9 (APC6) in complex with Hcn1 (Cdc26) shows Cdc16 forms a contiguous 14-TPR superhelix; its N-terminal TPR block mediates homo-dimerization through an interface structurally related to the Cdc27 dimerization domain, demonstrating both APC/C TPR subunits use a conserved homo-dimerization mechanism. The N-acetyl-Met of Hcn1 is enclosed within the Cut9 superhelix, protecting it from Doa10 ubiquitin ligase recognition.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with direct structural comparison to Cdc27, mechanistic interpretation validated by structure\",\n      \"pmids\": [\"20924356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of human APC3 (CDC27) alone and in complex with the C-terminal domain of APC16 reveals: (1) one APC16 binds asymmetrically to the symmetric APC3 dimer; (2) APC3's C-terminal IR-tail binding cleft is critical for coactivator (CDC20/CDH1) recruitment and APC/C-catalyzed ubiquitination; (3) APC16 recruits APC7 to APC3; (4) APC3's >200-residue phosphorylation loop is not required for ubiquitination in vitro.\",\n      \"method\": \"X-ray crystallography, biochemical ubiquitination assay, deletion/mutation analysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro ubiquitination assays with mutagenesis, multiple mechanistic findings in one study\",\n      \"pmids\": [\"25490258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Swm1/Apc13 stabilizes the association of Cdc16 and Cdc27 within the APC/C; deletion of SWM1 reduces the stable incorporation of these subunits into the complex and abolishes APC/C ubiquitin-ligase activity in vitro.\",\n      \"method\": \"Yeast genetics, co-immunoprecipitation, in vitro ubiquitination assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic deletion with biochemical readout (Co-IP and in vitro ligase assay), single lab\",\n      \"pmids\": [\"15060174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Microcephalin (MCPH1) C-terminal tandem BRCT domains bind CDC27 in a phosphorylation-dependent manner; crystal structure of MCPH1 C-BRCTs in complex with a phosphorylated CDC27 peptide defines the binding interface, and single amino acid mutations at this interface disrupt the interaction in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay, X-ray crystallography, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus orthogonal Co-IP/in vitro binding, multiple methods in one study\",\n      \"pmids\": [\"22139841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Phosphorylation of CDC27 by casein kinase II (CKII) in response to TGF-β signaling facilitates APC/C activation and subsequent SnoN degradation; shRNA depletion of CKII abolishes TGF-β-induced CDC27 phosphorylation and SnoN destruction, and a phosphorylation-resistant CDC27 S154A mutant attenuates TGF-β-induced growth inhibition.\",\n      \"method\": \"shRNA knockdown, site-directed mutagenesis (S154A), phosphorylation assay, co-immunoprecipitation, ubiquitination assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic/pharmacological perturbation plus phospho-mutant functional analysis, single lab, multiple methods\",\n      \"pmids\": [\"21209074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"C/EBPδ transcriptionally induces CDC27 (APC3) expression, which leads to APC/C-Cdh1-mediated polyubiquitination and proteasomal degradation of cyclin D1 (as well as cyclin B1, Skp2, and Plk-1); C/EBPδ-knockout MEFs have reduced Cdc27 and elevated cyclin D1, and silencing of CDC27 or Cdh1 in breast epithelial cells increases cyclin D1 protein levels.\",\n      \"method\": \"siRNA knockdown, C/EBPδ knockout MEFs, Western blotting, co-immunoprecipitation, ubiquitination assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus RNAi with biochemical ubiquitination readout, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"20439707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The RNA-binding protein HNRNP E1 (PCBP1) post-transcriptionally silences CDC27 translation in normal mammary epithelial cells; shRNA-mediated knockdown of HNRNP E1 leads to constitutive CDC27 expression, premature activation of the G2-M APC/C-CDC20 complex, aberrant degradation of CDH1/FZR1, and consequent mitotic aberrations and aneuploidy.\",\n      \"method\": \"shRNA knockdown, Western blotting, cell cycle analysis, aneuploidy scoring, co-immunoprecipitation\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular and cellular phenotype, single lab, multiple methods\",\n      \"pmids\": [\"27102006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The Drosophila mákos (mks) gene encodes the Cdc27 subunit of APC/C; mks mutant neuroblasts arrest in a metaphase-like state with elevated cyclin A and cyclin B. Loss of mks enhances centrosomal defects in polo hypomorphs (reduced γ-tubulin and CP190 at spindle poles). The metaphase arrest of mks mutants is not suppressed by bub1 spindle checkpoint mutations (confirming the checkpoint must act through APC/C), but is suppressed by mutations in twins/aar (PP2A regulatory subunit B55), indicating PP2A acts downstream of APC/C to initiate anaphase.\",\n      \"method\": \"Drosophila genetics, epistasis analysis (double mutants), immunofluorescence, immunohistochemistry\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple double mutant combinations and clear functional readouts, single lab\",\n      \"pmids\": [\"12953067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Two Cdk1 phosphorylation consensus sites on Drosophila Cdc27 (at P304 and P456) are jointly required for chromosomal localization of GFP::Cdc27 during mitosis and for APC/C function in vivo; the double proline-to-alanine mutant (P304A,P456A) fails to localize to mitotic chromosomes and cannot rescue cdc27 mutant phenotypes, while single mutants remain functional.\",\n      \"method\": \"Site-directed mutagenesis, GFP live imaging in Drosophila syncytial embryos, in vivo rescue assay, immunostaining for cyclin B and A\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with in vivo functional rescue and live imaging, single lab\",\n      \"pmids\": [\"17519285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Curcumin directly binds to and crosslinks CDC27/APC3, inhibiting APC/C ubiquitin ligase activity; cells with phosphorylated CDC27 (found in highly proliferating cells) are preferentially driven to apoptosis by curcumin treatment.\",\n      \"method\": \"Pull-down assay (curcumin-bead binding), in vitro APC/C ubiquitination assay, cell cycle profiling\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by pulldown plus in vitro activity assay, single lab\",\n      \"pmids\": [\"22280307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In Trypanosoma brucei, depletion of CDC27 by RNAi arrests procyclic-form cells in metaphase (two kinetoplasts, short metaphase-like spindle) and bloodstream-form cells in late anaphase, demonstrating an essential role of CDC27/APC/C in promoting anaphase in both life-cycle stages.\",\n      \"method\": \"RNA interference, FACS cell cycle analysis, fluorescence microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with defined mitotic phenotypes in two cell types, single lab\",\n      \"pmids\": [\"15994309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CDC27 knockdown in colorectal cancer cells causes G1/S arrest through accumulation of p21 (Cip1/Waf1), mediated via downregulation of ID1; CDC27 overexpression reduces p21 and promotes G1/S progression through ID1-dependent p21 suppression.\",\n      \"method\": \"shRNA knockdown, CDC27 overexpression, cell cycle analysis, Western blotting, rescue assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with pathway rescue experiments, single lab\",\n      \"pmids\": [\"26821069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In cisplatin-treated human cancer cells, Mad2B (Mad2L2) exists in a basal complex with APC/C subunit CDC27, DNA polymerase ζ (Rev3/Rev1); upon cisplatin-induced DNA damage, CDC20 is additionally recruited to this complex and APC/C ubiquitination activity is enhanced in a Mad2B-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, fluorescence microscopy (focus recruitment)\",\n      \"journal\": \"The Korean journal of physiology & pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus in vitro ubiquitination assay, single lab\",\n      \"pmids\": [\"37641805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDC27 is O-GlcNAcylated by OGT (O-GlcNAc transferase) in multiple myeloma cells; O-GlcNAcylation stabilizes CDC27 protein by blocking its degradation through the autophagy-lysosome pathway. Pharmacological inhibition of O-GlcNAcylation (OSMI-1) reduces CDC27 protein levels identified by mass spectrometry and immunoprecipitation.\",\n      \"method\": \"Mass spectrometry, immunoprecipitation, siRNA knockdown of OGT, pharmacological inhibition/accumulation of O-GlcNAcylation, Western blotting\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry identification of modification plus pharmacological and genetic perturbation, single lab\",\n      \"pmids\": [\"39984622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Human CDC27 (H-NUC) is a nuclear protein that binds to hypophosphorylated retinoblastoma protein (Rb) via two distinct regions: one overlapping the binding motif for SV40 large T antigen, and a second involving CDC27's TPR motifs. A temperature-sensitive point mutant (G640D) of CDC27 loses Rb binding at restrictive temperature.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay, temperature-sensitive mutagenesis, subcellular fractionation, DNA-binding assay\",\n      \"journal\": \"Cell growth & differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus in vitro binding and mutagenesis but single lab and functional significance not fully defined\",\n      \"pmids\": [\"7756179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cdc27 interacts with Elmo1 at the C-terminal region of Elmo1 that is essential for Dock1 association; the Elmo1-Dock1 interaction abrogates Elmo1-Cdc27 binding, but Cdc27 levels do not affect Dock1-Elmo1 interaction or Elmo1-Dock1-Rac-mediated phagocytosis.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, domain mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with domain mapping, single lab, limited functional follow-up\",\n      \"pmids\": [\"26882976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Nuclear-localized CTEN associates with the CDC27 gene promoter and transcriptionally activates CDC27 expression; CTEN overexpression with nuclear localization signals increases CDC27 mRNA and promoter activity, and CDC27 knockdown suppresses the CTEN-mediated increase in cell migration.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, shRNA knockdown, RT-qPCR, migration assay\",\n      \"journal\": \"Journal of physiology and biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP and reporter assay for transcriptional regulation, single lab, limited mechanistic depth\",\n      \"pmids\": [\"36399312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"cdc27 knockout in zebrafish causes craniofacial malformation, spine deformity, and cardiac edema mirroring hemifacial microsomia phenotypes; mechanistically, loss of cdc27 reduces neural crest cell (NCC) proliferation in pharyngeal arches and disrupts chondrocyte differentiation. Rescue by cdc27 mRNA injection or cdkn1a/tp53 knockout (but only partial rescue by sox9a mRNA) places cdc27 upstream of the p21/p53 pathway in pharyngeal arch development.\",\n      \"method\": \"CRISPR/Cas9 knockout in zebrafish, in situ hybridization, immunofluorescence (PH3), TUNEL assay, RNA sequencing, mRNA injection rescue, genetic epistasis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple orthogonal assays and epistasis rescue experiments, single lab\",\n      \"pmids\": [\"38731925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIX1 promotes nasopharyngeal carcinoma progression through the CDC27/cyclin B1 axis; SIX1 knockdown reduces CDC27 and cyclin B1 levels, and SIX1 overexpression increases them. The E3 ligase ITCH ubiquitinates SIX1 to promote its degradation, thereby suppressing CDC27-cyclin B1-driven tumor phenotypes.\",\n      \"method\": \"siRNA knockdown, Western blotting, co-immunoprecipitation, cell proliferation/migration/invasion assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-lab knockdown/overexpression study with Western blot readout; indirect pathway placement for CDC27\",\n      \"pmids\": [\"39406717\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDC27/APC3 is a core TPR-repeat subunit of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase that homo-dimerizes through a conserved TPR superhelix and serves as a structural hub recruiting coactivators (CDC20, CDH1) via its C-terminal IR-tail binding cleft; in mitosis, Cdk1-mediated phosphorylation of CDC27 directs its chromosomal localization and is required for full APC/C activity, while casein kinase II-mediated phosphorylation links TGF-β signaling to APC/C activation, O-GlcNAcylation by OGT stabilizes CDC27 protein by blocking autophagy-lysosomal degradation, and the APC/C-CDC27 complex catalyzes ubiquitination of cyclin B, securin, cyclin A, and other cell cycle regulators to drive the metaphase-to-anaphase transition and mitotic exit.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDC27 (APC3) is a core, structurally essential subunit of the anaphase-promoting complex/cyclosome (APC/C), a regulated ubiquitin-protein ligase that catalyzes mitosis-specific polyubiquitination of cyclin B and other cell cycle regulators to drive the metaphase-to-anaphase transition [#0]. Genetic loss of CDC27 orthologs arrests cells at a metaphase-like stage with elevated cyclins A and B across fission yeast, Drosophila, and trypanosomes, confirming its conserved and essential role in promoting anaphase [#1, #15, #18]. CDC27 is built from tandem tetratricopeptide (TPR) repeats that form a superhelix [#2], and crystallographic work establishes that this TPR domain mediates an evolutionarily conserved, functionally essential homo-dimerization shared with the related APC/C subunit Cdc16/APC6 [#7, #8]. Within the assembled complex CDC27 serves as a structural hub: its C-terminal IR-tail binding cleft recruits the coactivators CDC20 and CDH1 and is required for APC/C-catalyzed ubiquitination, while APC16 binds asymmetrically to the symmetric CDC27 dimer and bridges APC7 into the complex [#9]; stable incorporation of CDC27 itself depends on the accessory subunit Swm1/Apc13 [#10]. CDC27 activity and abundance are governed by multiple post-translational and regulatory inputs: Cdk1 phosphorylation at consensus sites directs its chromosomal localization and is required for full APC/C function [#16], dephosphorylated CDC27 specifically associates with kinetochores and chromosome arms during mitosis [#6], casein kinase II phosphorylation links TGF-\\u03b2 signaling to APC/C-driven SnoN degradation [#12], and O-GlcNAcylation by OGT stabilizes CDC27 by blocking autophagy-lysosomal degradation [#21]. Through APC/C-CDH1 it directs degradation of cyclin D1, cyclin B1, Skp2 and Plk-1 [#13], and its expression and translation are controlled transcriptionally by C/EBP\\u03b4 [#13] and post-transcriptionally by HNRNP E1, whose loss causes premature APC/C activation and aneuploidy [#14]. Zebrafish cdc27 knockout produces craniofacial and skeletal malformations resembling hemifacial microsomia via reduced neural crest proliferation acting upstream of the p21/p53 pathway [#25].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Established that the CDC27 ortholog is an essential nuclear factor required for mitotic spindle elongation, the first link of the gene to anaphase progression.\",\n      \"evidence\": \"Temperature-sensitive mutant analysis and nuclear fractionation of S. pombe nuc2+\",\n      \"pmids\": [\"3283148\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular activity unknown at this stage\", \"No connection yet to ubiquitination or a defined complex\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Defined the architecture of CDC27 as a TPR-repeat superhelix, identifying the structural module that would later mediate complex assembly and dimerization.\",\n      \"evidence\": \"Circular dichroism, limited proteolysis and in vitro DNA-binding of S. pombe nuc2+ protein\",\n      \"pmids\": [\"2297790\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of TPR repeats not yet established\", \"In vitro AT-rich DNA binding of uncertain physiological relevance\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Answered what CDC27 does biochemically by showing it is a subunit of the 20S APC ubiquitin ligase required for cyclin B ubiquitination, defining its core enzymatic context.\",\n      \"evidence\": \"Immunodepletion and immunopurification from Xenopus mitotic extracts with in vitro ubiquitination reconstitution\",\n      \"pmids\": [\"7736580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define CDC27's specific role within the complex\", \"Substrate range beyond cyclin B not addressed\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Extended CDC27 function beyond mitotic exit, showing it restricts DNA replication to once per cycle via APC/C-mediated proteolysis.\",\n      \"evidence\": \"Genetic screen and flow cytometry of S. cerevisiae conditional alleles\",\n      \"pmids\": [\"8620535\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"S-phase initiator substrate not identified\", \"Mechanism inferred from DNA overreplication phenotype\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Revealed a destruction-box-independent APC/C degradation route by which CDC27 controls coactivator Cdc20 stability, expanding regulatory logic of the complex.\",\n      \"evidence\": \"Yeast genetics and protein stability assays with CDC27/CDC23 mutants\",\n      \"pmids\": [\"9651679\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degron and recruitment mechanism undefined\", \"Single-organism evidence\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linked CDC27 phosphorylation state to spatial regulation, showing dephosphorylated CDC27 associates with kinetochores and chromosomes and is required to maintain metaphase.\",\n      \"evidence\": \"Immunofluorescence, chromosome fractionation, in vitro phosphorylation and antibody microinjection in human cells\",\n      \"pmids\": [\"12429948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Responsible kinases/phosphatases not fully defined\", \"Functional consequence of chromosomal pool unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified Cdk1 phosphorylation sites required for CDC27 chromosomal localization and APC/C function in vivo, connecting mitotic kinase activity to CDC27 targeting.\",\n      \"evidence\": \"Site-directed mutagenesis, GFP live imaging and rescue in Drosophila embryos\",\n      \"pmids\": [\"17519285\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether human CDC27 uses identical sites not addressed here\", \"Link between localization and catalytic activity correlative\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved the structural basis of CDC27 function, showing TPR-mediated homo-dimerization is conserved and essential and is shared with the APC6 subunit.\",\n      \"evidence\": \"X-ray crystallography of E. cuniculi Cdc27 and S. pombe Cdc16, with mutagenesis and in vivo complementation\",\n      \"pmids\": [\"20206185\", \"20924356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve coactivator-binding interface\", \"Human complex architecture inferred from fungal/microsporidian structures\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined CDC27 as the coactivator-recruiting hub by mapping its IR-tail binding cleft and its asymmetric engagement of APC16/APC7, explaining how it scaffolds the active ligase.\",\n      \"evidence\": \"Crystallography of human APC3 alone and with APC16, plus in vitro ubiquitination assays\",\n      \"pmids\": [\"25490258\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation loop function in vivo not resolved (dispensable in vitro)\", \"Dynamics of coactivator exchange not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established phosphorylation-dependent and signaling-coupled regulation of CDC27 through MCPH1 BRCT binding and CKII-mediated TGF-\\u03b2 linkage to APC/C activation.\",\n      \"evidence\": \"Crystallography/Co-IP of MCPH1\\u2013CDC27 and shRNA/phospho-mutant analysis of CKII\\u2013TGF-\\u03b2\\u2013SnoN axis\",\n      \"pmids\": [\"22139841\", \"21209074\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular consequence of MCPH1\\u2013CDC27 binding not fully defined\", \"CKII regulation single-lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed CDC27 under transcriptional and translational control coupled to cell cycle fidelity, showing C/EBP\\u03b4 induction and HNRNP E1 silencing govern its level to prevent aneuploidy.\",\n      \"evidence\": \"siRNA/KO, shRNA, ubiquitination and cell cycle/aneuploidy assays in mammalian cells\",\n      \"pmids\": [\"20439707\", \"27102006\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain to specific substrates partly correlative\", \"Single-lab observations\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified O-GlcNAcylation by OGT as a stabilizing modification that protects CDC27 from autophagy-lysosomal degradation, adding a metabolic input to CDC27 abundance.\",\n      \"evidence\": \"Mass spectrometry, IP, OGT siRNA and OSMI-1 inhibition in multiple myeloma cells\",\n      \"pmids\": [\"39984622\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GlcNAcylation sites not mapped\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a developmental requirement for CDC27, showing its loss causes craniofacial/skeletal malformation through reduced neural crest proliferation acting upstream of p21/p53.\",\n      \"evidence\": \"CRISPR knockout, in situ hybridization, PH3/TUNEL, RNA-seq and epistasis rescue in zebrafish\",\n      \"pmids\": [\"38731925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether phenotype reflects APC/C ubiquitination activity not directly tested\", \"Causal substrate linking CDC27 to p21/p53 not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse regulatory inputs to CDC27 (Cdk1, CKII, O-GlcNAc, transcriptional/translational control) are integrated to tune APC/C activity in specific physiological and disease contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified quantitative model of CDC27 regulation\", \"Mendelian disease causation in humans not established in this corpus\", \"Substrate selectivity contributions of CDC27 versus coactivators incompletely defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 9, 13]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [7, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 22]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [6, 16]},\n      {\"term_id\": \"GO:0005819\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 13, 15]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"complexes\": [\"APC/C (anaphase-promoting complex/cyclosome)\"],\n    \"partners\": [\"CDC16\", \"APC16\", \"CDC20\", \"CDH1/FZR1\", \"MCPH1\", \"PP5\", \"MAD2L2\", \"RB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}