{"gene":"CDC27","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":1995,"finding":"CDC27 (APC3) is a core subunit of the 20S anaphase-promoting complex (APC/C), a ubiquitin-protein ligase that catalyzes mitosis-specific ubiquitin conjugation to cyclin B, targeting it for destruction at anaphase onset. CDC27 antibody depletion abolishes APC activity, and immunopurified CDC27 complexes can reconstitute cyclin B ubiquitination with UBC4 and E1.","method":"Biochemical fractionation of Xenopus egg extracts, immunodepletion with anti-CDC27 antibodies, immunopurification and in vitro ubiquitination reconstitution assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro ubiquitination activity, multiple orthogonal methods, foundational paper with 843 citations","pmids":["7736580"],"is_preprint":false},{"year":1997,"finding":"The serine/threonine phosphatase PP5 physically interacts with CDC27 (and CDC16) through its N-terminal tetratricopeptide repeat (TPR) domain; the binding site on CDC27 maps to its C-terminal block of TPR repeats. PP5 colocalizes with CDC27 at the mitotic spindle apparatus, suggesting PP5 regulates APC/C activity via dephosphorylation.","method":"Yeast two-hybrid analysis, in vitro binding/pulldown assays, indirect immunofluorescence localization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2/3 — two-hybrid confirmed by in vitro binding and colocalization; single lab","pmids":["9405394"],"is_preprint":false},{"year":1998,"finding":"In budding yeast, CDC27 and CDC23 (APC subunits) are required for destruction-box-independent proteolysis of Cdc20 during S phase and early mitosis, establishing that Cdc20 is itself a substrate of the APC dependent on CDC27.","method":"Genetic analysis in S. cerevisiae; cell-cycle-regulated protein stability assays in cdc27 and cdc23 mutants","journal":"Current biology","confidence":"Medium","confidence_rationale":"Tier 2 — clean genetic epistasis in yeast with defined substrate and cell-cycle stage; single lab","pmids":["9651679"],"is_preprint":false},{"year":2002,"finding":"Dephosphorylated CDC27/APC3 localizes to kinetochores and chromosome arms during mitosis in mammalian cells, independent of microtubules. Only the dephosphorylated form associates with isolated chromosomes and is phosphorylated by chromosome-associated kinases in vitro. Microinjection of anti-Cdc27 antibody causes metaphase arrest and blocks the premature anaphase otherwise induced by anti-Mad2 antibody, placing APC/C CDC27 downstream of the spindle checkpoint.","method":"Immunofluorescence microscopy, chromosome isolation and fractionation, in vitro kinase assay, antibody microinjection into mammalian cells","journal":"Cell cycle","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (fractionation, functional microinjection, in vitro kinase assay) in a single study","pmids":["12429948"],"is_preprint":false},{"year":2004,"finding":"The small APC/C subunit Swm1/Apc13 promotes the stable association of CDC27 (and CDC16) within the APC/C complex; loss of Swm1 reduces APC/C ubiquitin ligase activity in vitro and delays APC/C-dependent cell cycle events in vivo.","method":"Yeast genetics, mass spectrometry interactome, in vitro ubiquitination assay, cross-species complementation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro ubiquitination assay combined with genetic and proteomic evidence, replicated across organisms","pmids":["15060174"],"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 the ability of CDC27 to complement S. cerevisiae cdc27 deletion in vivo, demonstrating the functional importance of CDC27 dimerization.","method":"X-ray crystallography, analytical ultracentrifugation/gel filtration, site-directed mutagenesis, yeast complementation assay","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with mutagenesis and in vivo functional validation","pmids":["20206185"],"is_preprint":false},{"year":2010,"finding":"CDC27 (APC3) and CDC16 (APC6/Cut9) both form homo-dimers through a conserved N-terminal TPR interface, as revealed by the crystal structure of S. pombe Cut9 in complex with Hcn1 (Cdc26). The acetylated N-terminal Met of Hcn1 is buried within the Cut9 TPR chamber, protecting Hcn1 from Doa10-mediated ubiquitin-dependent degradation.","method":"X-ray crystallography of S. pombe Cut9–Hcn1 complex","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure with structural and mechanistic insights into CDC27/CDC16 dimer architecture","pmids":["20924356"],"is_preprint":false},{"year":2010,"finding":"C/EBPδ transcriptionally induces CDC27 (APC3) expression, which then directs polyubiquitination and proteasomal degradation of cyclin D1 via APC/C-CDH1. Silencing of CDC27 or CDH1 in breast epithelial cells increases cyclin D1 protein levels; in C/EBPδ knockout MEFs, CDC27 and its activity toward cyclin D1 are reduced.","method":"siRNA/shRNA knockdown, overexpression, immunoprecipitation, in vitro ubiquitination assay, C/EBPδ knockout MEFs","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including in vitro ubiquitination, genetic KO, and rescue experiments","pmids":["20439707"],"is_preprint":false},{"year":2011,"finding":"The C-terminal tandem BRCT domains of microcephalin (MCPH1) bind phosphorylated CDC27 in a phosphorylation-dependent manner. The crystal structure of MCPH1 C-BRCTs in complex with a phospho-CDC27 peptide was determined; point mutations at the binding interface disrupted 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 — crystal structure with mutagenesis and in vivo validation; single study with multiple orthogonal methods","pmids":["22139841"],"is_preprint":false},{"year":2011,"finding":"Casein kinase II (CKII) phosphorylates CDC27 at Ser154 in response to TGF-β signaling, which activates APC/C to ubiquitinate and degrade SnoN. Knockdown of CKII abolishes TGF-β-induced CDC27 phosphorylation and SnoN degradation; a phosphorylation-resistant CDC27-S154A mutant attenuates TGF-β-induced growth inhibition.","method":"shRNA knockdown of CKII, phosphorylation-resistant mutagenesis (S154A), SnoN degradation assays, growth inhibition assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro phosphorylation with specific kinase, mutagenesis of phosphosite, and functional rescue experiments","pmids":["21209074"],"is_preprint":false},{"year":2012,"finding":"Curcumin directly binds to and crosslinks CDC27/APC3, inhibiting APC/C ubiquitin ligase activity and inducing apoptosis preferentially in cells containing phosphorylated CDC27 (i.e., highly proliferating/cancer cells).","method":"Curcumin pulldown assays, in vitro APC/C ubiquitination activity assay, cell cycle profiling","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding confirmed by pulldown, APC activity confirmed in vitro; single lab","pmids":["22280307"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of human APC3 (CDC27) Δloop domain alone and in complex with the C-terminal domain of APC16 reveals asymmetric binding of one APC16 molecule to the symmetric APC3 dimer. APC3's C-terminal IR tail-binding cleft recruits APC/C coactivators CDC20 and CDH1; APC3 also mediates recruitment of APC7. The APC3 phosphorylation loop is not required for APC/C-catalyzed ubiquitination in vitro.","method":"X-ray crystallography, domain mapping/biochemistry, in vitro APC/C ubiquitination assay","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with in vitro biochemical validation of IR tail and APC16/APC7 interactions","pmids":["25490258"],"is_preprint":false},{"year":2016,"finding":"The RNA-binding protein HNRNP E1/PCBP1 post-transcriptionally silences translation of the CDC27 mRNA in normal mammary epithelial cells. Loss of HNRNP E1 causes constitutive CDC27 expression, leading to premature activation of APC/C-CDC20, aberrant degradation of CDH1/FZR1, mitotic aberrations, and aneuploidy.","method":"shRNA knockdown of HNRNP E1, polysome profiling/translational assays, flow cytometry for aneuploidy, APC/C activity assays","journal":"Molecular cancer research","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway established by KD with multiple functional readouts including APC/C activity and aneuploidy","pmids":["27102006"],"is_preprint":false},{"year":2003,"finding":"In Drosophila, Cdc27 (mákos gene product) is required for APC/C-mediated degradation of cyclin A and cyclin B during mitosis; mks mutant neuroblasts arrest in a metaphase-like state with elevated levels of both cyclins. Cdk1 phosphorylation of Cdc27 is required for this function. Mutations in twins/aar (PP2A regulatory subunit) suppress the mks metaphase arrest, defining PP2A as a negative regulator acting downstream of APC/C-Cdc27.","method":"Drosophila genetics, immunostaining for cyclins, epistasis analysis with spindle checkpoint (bub1) and PP2A (twins/aar) mutants","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in Drosophila, replicated with multiple alleles and suppressor analysis","pmids":["12953067"],"is_preprint":false},{"year":2007,"finding":"Cdk1 phosphorylation at two conserved sites (Pro304 and Pro456 motifs) in Drosophila Cdc27 is required for its chromosomal localization during mitosis and for APC/C function in vivo. Double phosphorylation-site mutation (P304A, P456A) prevents chromosomal localization of GFP::Cdc27 and fails to rescue cdc27 mutant phenotypes, with accumulation of cyclin A and cyclin B.","method":"GFP::Cdc27 live imaging in syncytial Drosophila embryos, site-directed mutagenesis, in vivo complementation assay, immunoblotting for cyclins","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis combined with live imaging and in vivo functional rescue; mechanistically links Cdk1 phosphorylation to chromosomal localization and APC/C activity","pmids":["17519285"],"is_preprint":false},{"year":2016,"finding":"CDC27 downregulation in colorectal cancer cells causes G1/S arrest via accumulation of p21Cip1/Waf1, mediated through modulation of ID1 protein expression. Overexpression of CDC27 promotes G1/S transition by attenuating p21 through the ID1 pathway.","method":"shRNA knockdown and overexpression of CDC27, cell cycle flow cytometry, immunoblotting for p21 and ID1, rescue assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 — defined pathway (CDC27→ID1→p21→G1/S) by KD/OE with rescue, but no direct biochemical substrate assay","pmids":["26821069"],"is_preprint":false},{"year":2025,"finding":"O-GlcNAcylation of CDC27 by OGT maintains CDC27 protein stability by blocking its degradation via the autophagy-lysosome pathway (ALP). Inhibition of O-GlcNAcylation (OSMI-1 or OGT knockdown) reduces CDC27 protein levels in multiple myeloma cells; mass spectrometry confirmed O-GlcNAcylated CDC27 as a direct target of OSMI-1.","method":"siRNA knockdown of OGT, pharmacological inhibition (OSMI-1), pharmacological accumulation (Thiamet G), mass spectrometry, immunoprecipitation, autophagy/lysosome inhibitor assays","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 — mass spectrometry-confirmed O-GlcNAcylation with multiple pharmacological approaches; single lab","pmids":["39984622"],"is_preprint":false},{"year":2023,"finding":"Mad2B (Mad2L2/Rev7) forms a complex with CDC27 in undamaged cells together with Polζ subunits Rev3 and Rev1; following cisplatin-induced DNA damage, Cdc20 is additionally recruited to this complex. In vitro ubiquitination assay confirmed Mad2B-dependent activation of APC/C-Cdc20 following cisplatin treatment.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, immunofluorescence localization upon DNA damage","journal":"The Korean journal of physiology & pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP confirmed complex, in vitro ubiquitination confirms functional consequence; single lab","pmids":["37641805"],"is_preprint":false},{"year":1996,"finding":"In S. cerevisiae, CDC16 and CDC27 restrict DNA replication to once per cell cycle; temperature-sensitive mutants of CDC16 and CDC27 cause DNA overreplication (up to 8C DNA content) within a single cell cycle without requiring passage through mitosis, suggesting they target an S phase initiator for proteolysis.","method":"Yeast genetics, flow cytometry for DNA content, cell-cycle analysis","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 — clean genetic loss-of-function with specific cell-cycle phenotype; single study","pmids":["8620535"],"is_preprint":false},{"year":2016,"finding":"Elmo1 interacts with CDC27 through Elmo1's C-terminal region (essential for Dock1 association). Dock1 binding to Elmo1 abrogates Elmo1–CDC27 interaction, but CDC27 does not affect Elmo1–Dock1–Rac-mediated phagocytosis.","method":"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, pulldown assays, phagocytosis assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP/pulldown, limited functional follow-up showing CDC27 is not required for known Elmo function","pmids":["26882976"],"is_preprint":false}],"current_model":"CDC27/APC3 is a core TPR-containing subunit of the APC/C E3 ubiquitin ligase that homodimerizes via its N-terminal TPR superhelix, recruits coactivators (CDC20, CDH1) through its IR tail-binding cleft, and is activated by Cdk1- and CKII-mediated phosphorylation to catalyze K48-linked ubiquitination of mitotic substrates (cyclin B, cyclin A, securin, SnoN, cyclin D1), thereby driving the metaphase-to-anaphase transition, mitotic exit, and G1 progression; its chromosomal localization during mitosis depends on Cdk1 phosphorylation, its activity is modulated by PP5 and PP2A dephosphorylation, its protein stability is maintained by O-GlcNAcylation, and its translation is post-transcriptionally repressed by HNRNP E1."},"narrative":{"teleology":[{"year":1995,"claim":"Establishing that CDC27 is a catalytically essential subunit of the APC/C resolved the identity of the E3 ligase responsible for mitotic cyclin B ubiquitination.","evidence":"Immunodepletion and immunopurification from Xenopus egg extracts reconstituted cyclin B ubiquitination in vitro","pmids":["7736580"],"confidence":"High","gaps":["Specific contribution of CDC27 versus other APC/C subunits to substrate recognition was unknown","No structural information on CDC27 at this stage"]},{"year":1996,"claim":"Demonstrating that CDC27 mutants cause DNA overreplication in yeast revealed an APC/C role in restricting S-phase re-initiation, extending its function beyond anaphase onset.","evidence":"Temperature-sensitive cdc27 mutants in S. cerevisiae showed up to 8C DNA content by flow cytometry","pmids":["8620535"],"confidence":"Medium","gaps":["The specific APC/C substrate(s) responsible for licensing control were not identified","No direct measurement of APC/C activity in this context"]},{"year":1997,"claim":"Identification of PP5 as a CDC27-interacting phosphatase provided the first evidence for regulated dephosphorylation of APC/C subunits.","evidence":"Yeast two-hybrid, in vitro pulldown, and colocalization of PP5 with CDC27 at the mitotic spindle","pmids":["9405394"],"confidence":"Medium","gaps":["No direct demonstration that PP5 dephosphorylates CDC27 or alters APC/C activity","Functional consequence of PP5-CDC27 interaction on cell cycle was not tested"]},{"year":1998,"claim":"Showing that CDC27 is required for destruction-box-independent proteolysis of Cdc20 established that the APC/C coactivator is itself an APC/C substrate requiring CDC27.","evidence":"Genetic analysis of Cdc20 stability in S. cerevisiae cdc27 mutants","pmids":["9651679"],"confidence":"Medium","gaps":["Mechanism of destruction-box-independent recognition was not defined","Whether this reflects a direct CDC27-Cdc20 interaction or an indirect requirement was unclear"]},{"year":2002,"claim":"Demonstrating that dephosphorylated CDC27 localizes to kinetochores and that anti-CDC27 antibody injection causes metaphase arrest placed CDC27 functionally downstream of the spindle assembly checkpoint.","evidence":"Immunofluorescence, chromosome fractionation, and antibody microinjection in mammalian cells","pmids":["12429948"],"confidence":"High","gaps":["Identity of kinase(s) responsible for CDC27 phosphorylation at chromosomes was inferred but not directly shown","How phosphorylation state controls chromosome binding was not structurally resolved"]},{"year":2003,"claim":"Genetic epistasis in Drosophila established that Cdk1 phosphorylation of Cdc27 is required for cyclin A/B degradation and that PP2A acts as a downstream antagonist of APC/C-Cdc27.","evidence":"Drosophila cdc27 (mákos) mutant neuroblasts arrest in metaphase with elevated cyclins; PP2A (twins/aar) mutations suppress the arrest","pmids":["12953067"],"confidence":"High","gaps":["Direct phosphorylation sites on Drosophila Cdc27 were not mapped in this study","Whether PP2A acts directly on CDC27 or on APC/C substrates was ambiguous"]},{"year":2004,"claim":"Identification of Swm1/Apc13 as a factor required for stable CDC27 incorporation into APC/C revealed a hierarchical assembly dependency among APC/C subunits.","evidence":"Mass spectrometry, yeast genetics, and in vitro ubiquitination assays across species","pmids":["15060174"],"confidence":"High","gaps":["Structural basis of the Swm1-CDC27 stabilization was not determined"]},{"year":2007,"claim":"Mapping of two Cdk1 phosphorylation sites on Drosophila Cdc27 and showing that their mutation abolishes chromosomal localization and APC/C function provided the first mechanistic link between Cdk1 phosphorylation, CDC27 localization, and substrate degradation in vivo.","evidence":"GFP::Cdc27 phosphosite mutagenesis with live imaging and in vivo rescue in Drosophila embryos","pmids":["17519285"],"confidence":"High","gaps":["Whether these sites are conserved and functionally equivalent in mammalian CDC27 was not tested","Binding partner that recruits phospho-CDC27 to chromosomes was unknown"]},{"year":2010,"claim":"Crystal structures of CDC27 homologs revealed that CDC27 homodimerizes via an N-terminal TPR superhelix and that dimerization is essential for APC/C function, providing the first atomic-resolution view of APC/C subunit architecture.","evidence":"X-ray crystallography of E. cuniculi CDC27 and S. pombe Cut9-Hcn1 complex, validated by mutagenesis and yeast complementation","pmids":["20206185","20924356"],"confidence":"High","gaps":["Full-length human CDC27 structure was not yet available","How the dimer integrates into the full APC/C architecture was not resolved"]},{"year":2010,"claim":"Demonstrating that CDC27/APC/C-CDH1 ubiquitinates cyclin D1 downstream of C/EBPδ transcriptional induction expanded the APC/C substrate repertoire to G1 regulators.","evidence":"siRNA knockdown, in vitro ubiquitination assay, and C/EBPδ knockout MEFs","pmids":["20439707"],"confidence":"High","gaps":["Whether cyclin D1 is a direct CDC27-dependent substrate or requires additional specificity factors was not fully resolved"]},{"year":2011,"claim":"Crystallographic determination of the MCPH1 BRCT–phospho-CDC27 interaction identified a specific reader of CDC27 phosphorylation, linking microcephalin to APC/C regulation.","evidence":"X-ray crystallography of MCPH1 C-BRCT with phospho-CDC27 peptide, mutagenesis, co-immunoprecipitation","pmids":["22139841"],"confidence":"High","gaps":["Functional consequence of MCPH1-CDC27 interaction on APC/C activity or cell cycle progression was not defined"]},{"year":2011,"claim":"Identification of CKII-mediated Ser154 phosphorylation of CDC27 as the signal activating APC/C for SnoN degradation connected CDC27 to the TGF-β signaling pathway.","evidence":"CKII knockdown, CDC27-S154A mutagenesis, SnoN degradation and growth inhibition assays","pmids":["21209074"],"confidence":"High","gaps":["Whether CKII phosphorylation of CDC27 affects other APC/C substrates was not examined","Structural basis of how Ser154 phosphorylation activates APC/C was not resolved"]},{"year":2014,"claim":"The crystal structure of human APC3 (CDC27) in complex with APC16 revealed the asymmetric subunit interface and the C-terminal IR tail-binding cleft that recruits coactivators CDC20 and CDH1, defining CDC27 as the central coactivator docking platform.","evidence":"X-ray crystallography of human APC3Δloop alone and with APC16, domain mapping, in vitro ubiquitination assays","pmids":["25490258"],"confidence":"High","gaps":["Whether the phosphorylation loop has a regulatory role in vivo despite being dispensable in vitro was unresolved"]},{"year":2016,"claim":"Discovering that HNRNP E1 represses CDC27 mRNA translation revealed a post-transcriptional control mechanism; its loss deregulates APC/C activity, prematurely destroys CDH1, and causes aneuploidy.","evidence":"HNRNP E1 knockdown with polysome profiling, flow cytometry for ploidy, APC/C activity assays in mammary epithelial cells","pmids":["27102006"],"confidence":"High","gaps":["The RNA element in CDC27 mRNA recognized by HNRNP E1 was not mapped","Whether this regulatory axis operates in non-epithelial tissues was not tested"]},{"year":2023,"claim":"Showing that Mad2B/Rev7 forms a constitutive complex with CDC27 and that cisplatin-induced DNA damage recruits Cdc20 to activate APC/C linked the APC/C-CDC27 axis to the DNA damage response.","evidence":"Co-immunoprecipitation and in vitro ubiquitination assay following cisplatin treatment","pmids":["37641805"],"confidence":"Medium","gaps":["The physiological substrate(s) of Mad2B-activated APC/C-Cdc20 after DNA damage were not identified","Whether Mad2B directly contacts CDC27 or binds via another subunit was not resolved"]},{"year":2025,"claim":"Demonstrating that OGT-mediated O-GlcNAcylation stabilizes CDC27 by blocking autophagy-lysosome-dependent degradation revealed a nutrient-sensing input controlling APC/C subunit abundance.","evidence":"OGT knockdown, OSMI-1 pharmacological inhibition, mass spectrometry-confirmed O-GlcNAcylation, autophagy/lysosome inhibitor rescue in multiple myeloma cells","pmids":["39984622"],"confidence":"Medium","gaps":["Specific O-GlcNAcylation sites on CDC27 were not mapped","Whether O-GlcNAcylation affects CDC27 activity independently of stability was not tested"]},{"year":null,"claim":"It remains unknown how CDC27 phosphorylation, O-GlcNAcylation, and coactivator binding are coordinately regulated to tune APC/C activity across different cell cycle phases and signaling contexts, and no high-resolution structure of full-length human CDC27 within the complete APC/C complex has captured these regulatory modifications simultaneously.","evidence":"","pmids":[],"confidence":"Low","gaps":["No integrated structural model incorporating phosphorylation, O-GlcNAcylation, and coactivator binding on CDC27","Relative contributions of Cdk1 vs. CKII phosphorylation to APC/C activation in different contexts are not delineated","Mechanism by which phosphorylated CDC27 is recruited to chromosomes is structurally unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,7,9,11]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[5,6,11]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[3,14]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,8]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,3,13,14,12]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,7,9,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9]}],"complexes":["APC/C"],"partners":["CDC16","CDC20","CDH1","APC16","APC7","PP5","MCPH1","MAD2L2"],"other_free_text":[]},"mechanistic_narrative":"CDC27 (APC3) is a core TPR-repeat subunit of the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that drives mitotic progression by targeting cyclins, securin, and other substrates for proteasomal destruction. CDC27 homodimerizes through a conserved N-terminal TPR superhelix essential for function, and its C-terminal IR tail-binding cleft recruits the coactivators CDC20 and CDH1, while also mediating incorporation of APC16 and APC7 [PMID:7736580, PMID:20206185, PMID:25490258]. Cdk1 phosphorylation of CDC27 is required for its chromosomal localization during mitosis and for APC/C-dependent degradation of cyclin A and cyclin B, whereas casein kinase II phosphorylation at Ser154 activates APC/C toward the TGF-β effector SnoN; phosphatases PP5 and PP2A counteract these modifications [PMID:17519285, PMID:12953067, PMID:21209074, PMID:9405394]. CDC27 protein stability is maintained by O-GlcNAcylation that prevents autophagy-lysosome-mediated degradation, and its translation is post-transcriptionally repressed by HNRNP E1, whose loss causes constitutive APC/C activation, premature CDH1 destruction, and aneuploidy [PMID:39984622, PMID:27102006]."},"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 Essential","n_dependent_lines":1206,"n_total_lines":1208,"dependency_fraction":0.9983443708609272},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000004897","cell_line_id":"CID000232","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":"CDC26","stoichiometry":10.0},{"gene":"ANAPC7","stoichiometry":10.0},{"gene":"PYCR2","stoichiometry":4.0},{"gene":"ANAPC5","stoichiometry":4.0},{"gene":"ANAPC1","stoichiometry":4.0},{"gene":"ANAPC10","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000232","total_profiled":1310},"omim":[{"mim_id":"620078","title":"FAMILY WITH SEQUENCE SIMILARITY 168, MEMBER B; FAM168B","url":"https://www.omim.org/entry/620078"},{"mim_id":"614484","title":"ANAPHASE-PROMOTING COMPLEX, SUBUNIT 13; ANAPC13","url":"https://www.omim.org/entry/614484"},{"mim_id":"613745","title":"ANAPHASE-PROMOTING COMPLEX, SUBUNIT 10; ANAPC10","url":"https://www.omim.org/entry/613745"},{"mim_id":"613427","title":"ANAPHASE-PROMOTING COMPLEX, SUBUNIT 16; ANAPC16","url":"https://www.omim.org/entry/613427"},{"mim_id":"610874","title":"SPERMATOGENESIS AND CENTRIOLE-ASSOCIATED 1; SPATC1","url":"https://www.omim.org/entry/610874"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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\"CDC27 (APC3) is a core subunit of the 20S anaphase-promoting complex (APC/C), a ubiquitin-protein ligase that catalyzes mitosis-specific ubiquitin conjugation to cyclin B, targeting it for destruction at anaphase onset. CDC27 antibody depletion abolishes APC activity, and immunopurified CDC27 complexes can reconstitute cyclin B ubiquitination with UBC4 and E1.\",\n      \"method\": \"Biochemical fractionation of Xenopus egg extracts, immunodepletion with anti-CDC27 antibodies, immunopurification and in vitro ubiquitination reconstitution assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro ubiquitination activity, multiple orthogonal methods, foundational paper with 843 citations\",\n      \"pmids\": [\"7736580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The serine/threonine phosphatase PP5 physically interacts with CDC27 (and CDC16) through its N-terminal tetratricopeptide repeat (TPR) domain; the binding site on CDC27 maps to its C-terminal block of TPR repeats. PP5 colocalizes with CDC27 at the mitotic spindle apparatus, suggesting PP5 regulates APC/C activity via dephosphorylation.\",\n      \"method\": \"Yeast two-hybrid analysis, in vitro binding/pulldown assays, indirect immunofluorescence localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — two-hybrid confirmed by in vitro binding and colocalization; single lab\",\n      \"pmids\": [\"9405394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"In budding yeast, CDC27 and CDC23 (APC subunits) are required for destruction-box-independent proteolysis of Cdc20 during S phase and early mitosis, establishing that Cdc20 is itself a substrate of the APC dependent on CDC27.\",\n      \"method\": \"Genetic analysis in S. cerevisiae; cell-cycle-regulated protein stability assays in cdc27 and cdc23 mutants\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic epistasis in yeast with defined substrate and cell-cycle stage; single lab\",\n      \"pmids\": [\"9651679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Dephosphorylated CDC27/APC3 localizes to kinetochores and chromosome arms during mitosis in mammalian cells, independent of microtubules. Only the dephosphorylated form associates with isolated chromosomes and is phosphorylated by chromosome-associated kinases in vitro. Microinjection of anti-Cdc27 antibody causes metaphase arrest and blocks the premature anaphase otherwise induced by anti-Mad2 antibody, placing APC/C CDC27 downstream of the spindle checkpoint.\",\n      \"method\": \"Immunofluorescence microscopy, chromosome isolation and fractionation, in vitro kinase assay, antibody microinjection into mammalian cells\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (fractionation, functional microinjection, in vitro kinase assay) in a single study\",\n      \"pmids\": [\"12429948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The small APC/C subunit Swm1/Apc13 promotes the stable association of CDC27 (and CDC16) within the APC/C complex; loss of Swm1 reduces APC/C ubiquitin ligase activity in vitro and delays APC/C-dependent cell cycle events in vivo.\",\n      \"method\": \"Yeast genetics, mass spectrometry interactome, in vitro ubiquitination assay, cross-species complementation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro ubiquitination assay combined with genetic and proteomic evidence, replicated across organisms\",\n      \"pmids\": [\"15060174\"],\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 the ability of CDC27 to complement S. cerevisiae cdc27 deletion in vivo, demonstrating the functional importance of CDC27 dimerization.\",\n      \"method\": \"X-ray crystallography, analytical ultracentrifugation/gel filtration, site-directed mutagenesis, yeast complementation assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with mutagenesis and in vivo functional validation\",\n      \"pmids\": [\"20206185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CDC27 (APC3) and CDC16 (APC6/Cut9) both form homo-dimers through a conserved N-terminal TPR interface, as revealed by the crystal structure of S. pombe Cut9 in complex with Hcn1 (Cdc26). The acetylated N-terminal Met of Hcn1 is buried within the Cut9 TPR chamber, protecting Hcn1 from Doa10-mediated ubiquitin-dependent degradation.\",\n      \"method\": \"X-ray crystallography of S. pombe Cut9–Hcn1 complex\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with structural and mechanistic insights into CDC27/CDC16 dimer architecture\",\n      \"pmids\": [\"20924356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"C/EBPδ transcriptionally induces CDC27 (APC3) expression, which then directs polyubiquitination and proteasomal degradation of cyclin D1 via APC/C-CDH1. Silencing of CDC27 or CDH1 in breast epithelial cells increases cyclin D1 protein levels; in C/EBPδ knockout MEFs, CDC27 and its activity toward cyclin D1 are reduced.\",\n      \"method\": \"siRNA/shRNA knockdown, overexpression, immunoprecipitation, in vitro ubiquitination assay, C/EBPδ knockout MEFs\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including in vitro ubiquitination, genetic KO, and rescue experiments\",\n      \"pmids\": [\"20439707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The C-terminal tandem BRCT domains of microcephalin (MCPH1) bind phosphorylated CDC27 in a phosphorylation-dependent manner. The crystal structure of MCPH1 C-BRCTs in complex with a phospho-CDC27 peptide was determined; point mutations at the binding interface disrupted 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 — crystal structure with mutagenesis and in vivo validation; single study with multiple orthogonal methods\",\n      \"pmids\": [\"22139841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Casein kinase II (CKII) phosphorylates CDC27 at Ser154 in response to TGF-β signaling, which activates APC/C to ubiquitinate and degrade SnoN. Knockdown of CKII abolishes TGF-β-induced CDC27 phosphorylation and SnoN degradation; a phosphorylation-resistant CDC27-S154A mutant attenuates TGF-β-induced growth inhibition.\",\n      \"method\": \"shRNA knockdown of CKII, phosphorylation-resistant mutagenesis (S154A), SnoN degradation assays, growth inhibition assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro phosphorylation with specific kinase, mutagenesis of phosphosite, and functional rescue experiments\",\n      \"pmids\": [\"21209074\"],\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 and inducing apoptosis preferentially in cells containing phosphorylated CDC27 (i.e., highly proliferating/cancer cells).\",\n      \"method\": \"Curcumin pulldown assays, in vitro APC/C ubiquitination activity assay, cell cycle profiling\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding confirmed by pulldown, APC activity confirmed in vitro; single lab\",\n      \"pmids\": [\"22280307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of human APC3 (CDC27) Δloop domain alone and in complex with the C-terminal domain of APC16 reveals asymmetric binding of one APC16 molecule to the symmetric APC3 dimer. APC3's C-terminal IR tail-binding cleft recruits APC/C coactivators CDC20 and CDH1; APC3 also mediates recruitment of APC7. The APC3 phosphorylation loop is not required for APC/C-catalyzed ubiquitination in vitro.\",\n      \"method\": \"X-ray crystallography, domain mapping/biochemistry, in vitro APC/C ubiquitination assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with in vitro biochemical validation of IR tail and APC16/APC7 interactions\",\n      \"pmids\": [\"25490258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The RNA-binding protein HNRNP E1/PCBP1 post-transcriptionally silences translation of the CDC27 mRNA in normal mammary epithelial cells. Loss of HNRNP E1 causes constitutive CDC27 expression, leading to premature activation of APC/C-CDC20, aberrant degradation of CDH1/FZR1, mitotic aberrations, and aneuploidy.\",\n      \"method\": \"shRNA knockdown of HNRNP E1, polysome profiling/translational assays, flow cytometry for aneuploidy, APC/C activity assays\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway established by KD with multiple functional readouts including APC/C activity and aneuploidy\",\n      \"pmids\": [\"27102006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In Drosophila, Cdc27 (mákos gene product) is required for APC/C-mediated degradation of cyclin A and cyclin B during mitosis; mks mutant neuroblasts arrest in a metaphase-like state with elevated levels of both cyclins. Cdk1 phosphorylation of Cdc27 is required for this function. Mutations in twins/aar (PP2A regulatory subunit) suppress the mks metaphase arrest, defining PP2A as a negative regulator acting downstream of APC/C-Cdc27.\",\n      \"method\": \"Drosophila genetics, immunostaining for cyclins, epistasis analysis with spindle checkpoint (bub1) and PP2A (twins/aar) mutants\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in Drosophila, replicated with multiple alleles and suppressor analysis\",\n      \"pmids\": [\"12953067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cdk1 phosphorylation at two conserved sites (Pro304 and Pro456 motifs) in Drosophila Cdc27 is required for its chromosomal localization during mitosis and for APC/C function in vivo. Double phosphorylation-site mutation (P304A, P456A) prevents chromosomal localization of GFP::Cdc27 and fails to rescue cdc27 mutant phenotypes, with accumulation of cyclin A and cyclin B.\",\n      \"method\": \"GFP::Cdc27 live imaging in syncytial Drosophila embryos, site-directed mutagenesis, in vivo complementation assay, immunoblotting for cyclins\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis combined with live imaging and in vivo functional rescue; mechanistically links Cdk1 phosphorylation to chromosomal localization and APC/C activity\",\n      \"pmids\": [\"17519285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CDC27 downregulation in colorectal cancer cells causes G1/S arrest via accumulation of p21Cip1/Waf1, mediated through modulation of ID1 protein expression. Overexpression of CDC27 promotes G1/S transition by attenuating p21 through the ID1 pathway.\",\n      \"method\": \"shRNA knockdown and overexpression of CDC27, cell cycle flow cytometry, immunoblotting for p21 and ID1, rescue assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — defined pathway (CDC27→ID1→p21→G1/S) by KD/OE with rescue, but no direct biochemical substrate assay\",\n      \"pmids\": [\"26821069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"O-GlcNAcylation of CDC27 by OGT maintains CDC27 protein stability by blocking its degradation via the autophagy-lysosome pathway (ALP). Inhibition of O-GlcNAcylation (OSMI-1 or OGT knockdown) reduces CDC27 protein levels in multiple myeloma cells; mass spectrometry confirmed O-GlcNAcylated CDC27 as a direct target of OSMI-1.\",\n      \"method\": \"siRNA knockdown of OGT, pharmacological inhibition (OSMI-1), pharmacological accumulation (Thiamet G), mass spectrometry, immunoprecipitation, autophagy/lysosome inhibitor assays\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mass spectrometry-confirmed O-GlcNAcylation with multiple pharmacological approaches; single lab\",\n      \"pmids\": [\"39984622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Mad2B (Mad2L2/Rev7) forms a complex with CDC27 in undamaged cells together with Polζ subunits Rev3 and Rev1; following cisplatin-induced DNA damage, Cdc20 is additionally recruited to this complex. In vitro ubiquitination assay confirmed Mad2B-dependent activation of APC/C-Cdc20 following cisplatin treatment.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, immunofluorescence localization upon DNA damage\",\n      \"journal\": \"The Korean journal of physiology & pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP confirmed complex, in vitro ubiquitination confirms functional consequence; single lab\",\n      \"pmids\": [\"37641805\"],\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; temperature-sensitive mutants of CDC16 and CDC27 cause DNA overreplication (up to 8C DNA content) within a single cell cycle without requiring passage through mitosis, suggesting they target an S phase initiator for proteolysis.\",\n      \"method\": \"Yeast genetics, flow cytometry for DNA content, cell-cycle analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic loss-of-function with specific cell-cycle phenotype; single study\",\n      \"pmids\": [\"8620535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Elmo1 interacts with CDC27 through Elmo1's C-terminal region (essential for Dock1 association). Dock1 binding to Elmo1 abrogates Elmo1–CDC27 interaction, but CDC27 does not affect Elmo1–Dock1–Rac-mediated phagocytosis.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, pulldown assays, phagocytosis assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP/pulldown, limited functional follow-up showing CDC27 is not required for known Elmo function\",\n      \"pmids\": [\"26882976\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDC27/APC3 is a core TPR-containing subunit of the APC/C E3 ubiquitin ligase that homodimerizes via its N-terminal TPR superhelix, recruits coactivators (CDC20, CDH1) through its IR tail-binding cleft, and is activated by Cdk1- and CKII-mediated phosphorylation to catalyze K48-linked ubiquitination of mitotic substrates (cyclin B, cyclin A, securin, SnoN, cyclin D1), thereby driving the metaphase-to-anaphase transition, mitotic exit, and G1 progression; its chromosomal localization during mitosis depends on Cdk1 phosphorylation, its activity is modulated by PP5 and PP2A dephosphorylation, its protein stability is maintained by O-GlcNAcylation, and its translation is post-transcriptionally repressed by HNRNP E1.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CDC27 (APC3) is a core TPR-repeat subunit of the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that drives mitotic progression by targeting cyclins, securin, and other substrates for proteasomal destruction. CDC27 homodimerizes through a conserved N-terminal TPR superhelix essential for function, and its C-terminal IR tail-binding cleft recruits the coactivators CDC20 and CDH1, while also mediating incorporation of APC16 and APC7 [PMID:7736580, PMID:20206185, PMID:25490258]. Cdk1 phosphorylation of CDC27 is required for its chromosomal localization during mitosis and for APC/C-dependent degradation of cyclin A and cyclin B, whereas casein kinase II phosphorylation at Ser154 activates APC/C toward the TGF-β effector SnoN; phosphatases PP5 and PP2A counteract these modifications [PMID:17519285, PMID:12953067, PMID:21209074, PMID:9405394]. CDC27 protein stability is maintained by O-GlcNAcylation that prevents autophagy-lysosome-mediated degradation, and its translation is post-transcriptionally repressed by HNRNP E1, whose loss causes constitutive APC/C activation, premature CDH1 destruction, and aneuploidy [PMID:39984622, PMID:27102006].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing that CDC27 is a catalytically essential subunit of the APC/C resolved the identity of the E3 ligase responsible for mitotic cyclin B ubiquitination.\",\n      \"evidence\": \"Immunodepletion and immunopurification from Xenopus egg extracts reconstituted cyclin B ubiquitination in vitro\",\n      \"pmids\": [\"7736580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific contribution of CDC27 versus other APC/C subunits to substrate recognition was unknown\", \"No structural information on CDC27 at this stage\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrating that CDC27 mutants cause DNA overreplication in yeast revealed an APC/C role in restricting S-phase re-initiation, extending its function beyond anaphase onset.\",\n      \"evidence\": \"Temperature-sensitive cdc27 mutants in S. cerevisiae showed up to 8C DNA content by flow cytometry\",\n      \"pmids\": [\"8620535\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The specific APC/C substrate(s) responsible for licensing control were not identified\", \"No direct measurement of APC/C activity in this context\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of PP5 as a CDC27-interacting phosphatase provided the first evidence for regulated dephosphorylation of APC/C subunits.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro pulldown, and colocalization of PP5 with CDC27 at the mitotic spindle\",\n      \"pmids\": [\"9405394\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct demonstration that PP5 dephosphorylates CDC27 or alters APC/C activity\", \"Functional consequence of PP5-CDC27 interaction on cell cycle was not tested\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showing that CDC27 is required for destruction-box-independent proteolysis of Cdc20 established that the APC/C coactivator is itself an APC/C substrate requiring CDC27.\",\n      \"evidence\": \"Genetic analysis of Cdc20 stability in S. cerevisiae cdc27 mutants\",\n      \"pmids\": [\"9651679\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of destruction-box-independent recognition was not defined\", \"Whether this reflects a direct CDC27-Cdc20 interaction or an indirect requirement was unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrating that dephosphorylated CDC27 localizes to kinetochores and that anti-CDC27 antibody injection causes metaphase arrest placed CDC27 functionally downstream of the spindle assembly checkpoint.\",\n      \"evidence\": \"Immunofluorescence, chromosome fractionation, and antibody microinjection in mammalian cells\",\n      \"pmids\": [\"12429948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of kinase(s) responsible for CDC27 phosphorylation at chromosomes was inferred but not directly shown\", \"How phosphorylation state controls chromosome binding was not structurally resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Genetic epistasis in Drosophila established that Cdk1 phosphorylation of Cdc27 is required for cyclin A/B degradation and that PP2A acts as a downstream antagonist of APC/C-Cdc27.\",\n      \"evidence\": \"Drosophila cdc27 (mákos) mutant neuroblasts arrest in metaphase with elevated cyclins; PP2A (twins/aar) mutations suppress the arrest\",\n      \"pmids\": [\"12953067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phosphorylation sites on Drosophila Cdc27 were not mapped in this study\", \"Whether PP2A acts directly on CDC27 or on APC/C substrates was ambiguous\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of Swm1/Apc13 as a factor required for stable CDC27 incorporation into APC/C revealed a hierarchical assembly dependency among APC/C subunits.\",\n      \"evidence\": \"Mass spectrometry, yeast genetics, and in vitro ubiquitination assays across species\",\n      \"pmids\": [\"15060174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the Swm1-CDC27 stabilization was not determined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapping of two Cdk1 phosphorylation sites on Drosophila Cdc27 and showing that their mutation abolishes chromosomal localization and APC/C function provided the first mechanistic link between Cdk1 phosphorylation, CDC27 localization, and substrate degradation in vivo.\",\n      \"evidence\": \"GFP::Cdc27 phosphosite mutagenesis with live imaging and in vivo rescue in Drosophila embryos\",\n      \"pmids\": [\"17519285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether these sites are conserved and functionally equivalent in mammalian CDC27 was not tested\", \"Binding partner that recruits phospho-CDC27 to chromosomes was unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Crystal structures of CDC27 homologs revealed that CDC27 homodimerizes via an N-terminal TPR superhelix and that dimerization is essential for APC/C function, providing the first atomic-resolution view of APC/C subunit architecture.\",\n      \"evidence\": \"X-ray crystallography of E. cuniculi CDC27 and S. pombe Cut9-Hcn1 complex, validated by mutagenesis and yeast complementation\",\n      \"pmids\": [\"20206185\", \"20924356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length human CDC27 structure was not yet available\", \"How the dimer integrates into the full APC/C architecture was not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that CDC27/APC/C-CDH1 ubiquitinates cyclin D1 downstream of C/EBPδ transcriptional induction expanded the APC/C substrate repertoire to G1 regulators.\",\n      \"evidence\": \"siRNA knockdown, in vitro ubiquitination assay, and C/EBPδ knockout MEFs\",\n      \"pmids\": [\"20439707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cyclin D1 is a direct CDC27-dependent substrate or requires additional specificity factors was not fully resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Crystallographic determination of the MCPH1 BRCT–phospho-CDC27 interaction identified a specific reader of CDC27 phosphorylation, linking microcephalin to APC/C regulation.\",\n      \"evidence\": \"X-ray crystallography of MCPH1 C-BRCT with phospho-CDC27 peptide, mutagenesis, co-immunoprecipitation\",\n      \"pmids\": [\"22139841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of MCPH1-CDC27 interaction on APC/C activity or cell cycle progression was not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of CKII-mediated Ser154 phosphorylation of CDC27 as the signal activating APC/C for SnoN degradation connected CDC27 to the TGF-β signaling pathway.\",\n      \"evidence\": \"CKII knockdown, CDC27-S154A mutagenesis, SnoN degradation and growth inhibition assays\",\n      \"pmids\": [\"21209074\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CKII phosphorylation of CDC27 affects other APC/C substrates was not examined\", \"Structural basis of how Ser154 phosphorylation activates APC/C was not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The crystal structure of human APC3 (CDC27) in complex with APC16 revealed the asymmetric subunit interface and the C-terminal IR tail-binding cleft that recruits coactivators CDC20 and CDH1, defining CDC27 as the central coactivator docking platform.\",\n      \"evidence\": \"X-ray crystallography of human APC3Δloop alone and with APC16, domain mapping, in vitro ubiquitination assays\",\n      \"pmids\": [\"25490258\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the phosphorylation loop has a regulatory role in vivo despite being dispensable in vitro was unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovering that HNRNP E1 represses CDC27 mRNA translation revealed a post-transcriptional control mechanism; its loss deregulates APC/C activity, prematurely destroys CDH1, and causes aneuploidy.\",\n      \"evidence\": \"HNRNP E1 knockdown with polysome profiling, flow cytometry for ploidy, APC/C activity assays in mammary epithelial cells\",\n      \"pmids\": [\"27102006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The RNA element in CDC27 mRNA recognized by HNRNP E1 was not mapped\", \"Whether this regulatory axis operates in non-epithelial tissues was not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing that Mad2B/Rev7 forms a constitutive complex with CDC27 and that cisplatin-induced DNA damage recruits Cdc20 to activate APC/C linked the APC/C-CDC27 axis to the DNA damage response.\",\n      \"evidence\": \"Co-immunoprecipitation and in vitro ubiquitination assay following cisplatin treatment\",\n      \"pmids\": [\"37641805\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The physiological substrate(s) of Mad2B-activated APC/C-Cdc20 after DNA damage were not identified\", \"Whether Mad2B directly contacts CDC27 or binds via another subunit was not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that OGT-mediated O-GlcNAcylation stabilizes CDC27 by blocking autophagy-lysosome-dependent degradation revealed a nutrient-sensing input controlling APC/C subunit abundance.\",\n      \"evidence\": \"OGT knockdown, OSMI-1 pharmacological inhibition, mass spectrometry-confirmed O-GlcNAcylation, autophagy/lysosome inhibitor rescue in multiple myeloma cells\",\n      \"pmids\": [\"39984622\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific O-GlcNAcylation sites on CDC27 were not mapped\", \"Whether O-GlcNAcylation affects CDC27 activity independently of stability was not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how CDC27 phosphorylation, O-GlcNAcylation, and coactivator binding are coordinately regulated to tune APC/C activity across different cell cycle phases and signaling contexts, and no high-resolution structure of full-length human CDC27 within the complete APC/C complex has captured these regulatory modifications simultaneously.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No integrated structural model incorporating phosphorylation, O-GlcNAcylation, and coactivator binding on CDC27\", \"Relative contributions of Cdk1 vs. CKII phosphorylation to APC/C activation in different contexts are not delineated\", \"Mechanism by which phosphorylated CDC27 is recruited to chromosomes is structurally unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 7, 9, 11]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [5, 6, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [3, 14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 3, 13, 14, 12]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 7, 9, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\"APC/C\"],\n    \"partners\": [\"CDC16\", \"CDC20\", \"CDH1\", \"APC16\", \"APC7\", \"PP5\", \"MCPH1\", \"MAD2L2\"],\n    \"other_free_text\": []\n  }\n}\n```"}