{"gene":"CDC20","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1998,"finding":"hMAD2 forms a ternary hMAD2-CDC20-APC complex that inhibits APC ubiquitin ligase activity. Only the MAD2 tetramer (not monomer) inhibits APC activation, demonstrating that MAD2 binding alone is insufficient for inhibition and that MAD2 oligomeric state matters. Three forms of mitotic APC were identified: inactive MAD2-CDC20-APC at metaphase, active CDC20-APC at anaphase, and CDH1-APC in G1.","method":"In vitro reconstitution with recombinant proteins, Xenopus embryo microinjection, immunoprecipitation","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with recombinant proteins, functional validation in Xenopus embryos, multiple orthogonal methods","pmids":["9637688"],"is_preprint":false},{"year":1998,"finding":"Mammalian p55CDC (CDC20) localizes to kinetochores from late prophase to telophase, to spindle microtubules and poles, and to the cytoplasm. In M-phase (but not interphase) extracts, p55CDC co-immunoprecipitates with APC components CDC27 and CDC16, and with MAD2. p55CDC is required for the association of MAD2 with CDC27 and CDC16, acting as a bridge between MAD2 and the APC/C.","method":"Immunofluorescence, GFP chimera live imaging, co-immunoprecipitation from HeLa cell extracts, antibody microinjection","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, direct localization by live imaging and IF, functional antibody injection, multiple orthogonal methods","pmids":["9628895"],"is_preprint":false},{"year":1994,"finding":"p55CDC (CDC20) is expressed in cycling mammalian cells and is phosphorylated during cell division. Immunoprecipitates of p55CDC contain associated kinase activity that fluctuates during the cell cycle (peaking at M phase), indicating p55CDC associates with a cell cycle-regulated kinase complex via its seven WD repeats.","method":"Immunoprecipitation, kinase assay, antisense transfection, immunolocalization","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, kinase co-IP without identification of the kinase, multiple methods but indirect","pmids":["7513050"],"is_preprint":false},{"year":1997,"finding":"p55CDC protein levels are highest at M phase and lowest in G1. Its degradation at the M/G1 transition is mediated by the 26S proteasome (inhibition of the proteasome prevents both mitotic exit and loss of p55CDC). Dynamic changes in p55CDC localization occur as cells transit mitosis.","method":"Cell synchronization, proteasome inhibitor treatment, immunolocalization, Western blot","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteasome inhibitor functional experiment with localization data, single lab","pmids":["9353311"],"is_preprint":false},{"year":1998,"finding":"MAD2 associates with the APC component CDC27 transiently during early normal mitosis (not only upon checkpoint activation), and this association requires p55CDC (CDC20), forming a MAD2/p55CDC/CDC27 ternary complex. A MAD2/CDC27 complex that forms independently of p55CDC was also detected.","method":"Co-immunoprecipitation from mammalian cells at different cell cycle stages","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP across multiple cell cycle stages, single lab, single primary method","pmids":["9736712"],"is_preprint":false},{"year":2001,"finding":"CDC20 (and CDH1) directly bind APC/C substrates via their N-termini, independent of APC/C. The N-terminus of CDC20 confers substrate specificity. Active chimeras swapping N-termini demonstrate that the N-terminus is the specificity determinant for substrate recognition.","method":"In vitro binding assays, chimeric protein construction, ubiquitination assays in the absence of APC/C","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis/chimeras, direct substrate binding demonstrated independent of APC","pmids":["11562349"],"is_preprint":false},{"year":2003,"finding":"Xenopus CDC20 is phosphorylated at Ser50, Thr64, Thr68, and Thr79 during mitosis; MAPK contributes to phosphorylation at Thr64 or Thr68. Phosphorylation-deficient CDC20 mutants activate APC/C normally but fail to respond to spindle checkpoint signals due to reduced affinity for spindle checkpoint proteins (BubR1, Bub3, Mad2). Thus, the spindle checkpoint arrests cells by inhibiting fully-phosphorylated CDC20.","method":"In vitro kinase assays, Xenopus egg extract APC/C ubiquitination assays, phospho-site mutagenesis, checkpoint binding assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, site-directed mutagenesis, functional checkpoint assays in Xenopus extracts","pmids":["12855955"],"is_preprint":false},{"year":2004,"finding":"In budding yeast, the PKA pathway supports Chk1 in restraining anaphase by phosphorylating Cdc20 on PKA consensus sites after DNA damage. This phosphorylation requires Mec1 (ATR ortholog) and PKA catalytic subunits Tpk1/Tpk2. Phosphorylation-defective Cdc20 mutants accelerate securin and Clb2 destruction and allow Cdc20 to interact with Clb2 under checkpoint conditions.","method":"Genetic epistasis, phospho-site mutagenesis, in vivo degradation assays, co-immunoprecipitation in yeast","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple mutants, phospho-mutagenesis, co-IP, yeast ortholog study","pmids":["14743219"],"is_preprint":false},{"year":2008,"finding":"CDC20 is rate-limiting for cyclin A destruction and binds cyclin A efficiently before and during mitosis. The cyclin A-CDC20 complex has little associated Mad2, enabling spindle-checkpoint-independent cyclin A degradation. Cks protein binding to the cyclin A complex is additionally required for its checkpoint-independent degradation by APC/C-CDC20.","method":"Co-immunoprecipitation, in vitro ubiquitination assays, RNA interference, cell synchronization","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, in vitro ubiquitination, RNAi phenotype, multiple orthogonal methods","pmids":["18471975"],"is_preprint":false},{"year":2009,"finding":"CDC20-APC plays an essential role in dendrite morphogenesis in postmitotic neurons. CDC20 is enriched at the centrosome in neurons, and centrosomal localization is critical for this function. HDAC6 promotes polyubiquitination of CDC20, stimulates centrosomal CDC20-APC activity, and drives dendrite differentiation.","method":"Knockdown in cerebellar slices and in vivo in rats, live imaging for centrosomal localization, ubiquitination assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockdown with specific phenotype, centrosomal localization tied to function, ubiquitination assay, multiple orthogonal methods","pmids":["19167333"],"is_preprint":false},{"year":2009,"finding":"CDC20-APC triggers degradation of the transcription factor NeuroD2 to promote presynaptic differentiation in postmitotic neurons. NeuroD2's target gene Complexin II mediates its suppression of presynaptic differentiation.","method":"Knockdown in primary neurons and rat cerebellar cortex in vivo, ubiquitination assays, genetic epistasis","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockdown, identification of substrate NeuroD2, epistasis with Complexin II, multiple orthogonal methods","pmids":["19900895"],"is_preprint":false},{"year":1999,"finding":"CDC20 associates with the kinase Aurora2/Aik in HeLa cells. CDC20-associated MBP kinase activity peaks in early M phase (embryonic cells) or G2 phase (somatic cells). The association suggests that Aurora2/Aik carries out or regulates some CDC20 function.","method":"Co-immunoprecipitation from HeLa cells, kinase assay with MBP substrate","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP identifying Aurora2/Aik as CDC20-associated kinase, kinase assay, single lab","pmids":["10377410"],"is_preprint":false},{"year":2000,"finding":"CDC20 (p55CDC) directly interacts with BUBR1 as shown by yeast two-hybrid, GST pulldown, and co-immunoprecipitation. BUBR1 phosphorylates p55CDC in vitro, and this phosphorylation correlates with spindle checkpoint activation. Spindle checkpoint activation by nocodazole enhances the p55CDC-BUBR1 association.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation from HeLa cells, in vitro kinase assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — three independent binding methods (Y2H, GST pulldown, co-IP), in vitro kinase assay, functional correlation","pmids":["11030144"],"is_preprint":false},{"year":2007,"finding":"p53 transcriptionally represses CDC20 expression through binding to a consensus p53-binding site in the CDC20 promoter and through CDE/CHR elements. This repression occurs in response to genotoxic stress in a p53- and p21-dependent manner. siRNA-mediated silencing of p53 induces CDC20 expression in normal human dermal fibroblasts.","method":"Reporter assays, ChIP, siRNA knockdown, expression analysis after genotoxic stress","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct p53 binding to CDC20 promoter, functional reporter assay, single lab","pmids":["17873905"],"is_preprint":false},{"year":2009,"finding":"p53 binds directly to a consensus site in the CDC20 promoter and causes chromatin remodeling to repress CDC20 transcription. p53 also downregulates CDC20 through CDE/CHR elements in a p21-independent manner under p53-overexpression conditions. The CCAAT elements in the CDC20 promoter are not used by p53 for repression.","method":"ChIP, promoter reporter assay, chromatin remodeling analysis, p53 binding site mutagenesis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP evidence of p53-promoter binding, chromatin remodeling, single lab","pmids":["19273532"],"is_preprint":false},{"year":2010,"finding":"Cdc20 is critical for meiosis I in female mice. Cdc20 hypomorphic females produce aneuploid gametes due to chromosome lagging and misalignment during meiosis I. Cyclin B1, cyclin A2, and securin are inefficiently degraded in metaphase I, and anaphase I onset is markedly delayed, demonstrating Cdc20's role in APC/C activation during female meiosis.","method":"Hypomorphic mouse model, chromosome analysis, immunostaining, live oocyte imaging","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model, multiple substrates examined, direct meiotic phenotype with mechanistic substrate analysis","pmids":["20941357"],"is_preprint":false},{"year":2011,"finding":"CDC20 undergoes APC/C-dependent autoubiquitination in cis (intramolecular mechanism) while bound to its activator-binding site on the APC/C core, independent of Cdc20's C-box. This cell-cycle-regulated mechanism contributes to the decline of CDC20 levels after anaphase. High substrate levels in vitro reduce Cdc20 autoubiquitination.","method":"In vitro ubiquitination assays, cell cycle synchronization, mutagenesis","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of autoubiquitination, mutagenesis distinguishing in cis from in trans mechanism","pmids":["22079111"],"is_preprint":false},{"year":2012,"finding":"APC15 is required for APC/C(MCC)-dependent CDC20 autoubiquitylation and degradation, and for timely anaphase initiation. APC15 is located near the APC/C MCC-binding site and is dispensable for substrate ubiquitylation by APC/C(CDC20) or APC/C(CDH1). CDC20 autoubiquitylation promotes MCC disassembly.","method":"RNAi depletion, in vitro ubiquitylation assays with recombinant human APC/C, cell biology","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted human APC/C system, RNAi phenotype, multiple orthogonal methods identifying APC15's specific role","pmids":["23007861"],"is_preprint":false},{"year":2012,"finding":"Mad2 inhibits CDC20 by binding directly to a site required for CDC20 to bind the APC/C. Mad2 and the APC/C compete for CDC20 in vitro, and a CDC20 mutant that does not bind stably to Mad2 abrogates the SAC in vivo. This reveals a second mechanism by which SAC inhibits APC/C (beyond pseudosubstrate inhibition).","method":"In vitro competition binding assay, mutagenesis, in vivo checkpoint assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro competition assay plus in vivo mutagenesis validating functional consequence, multiple orthogonal methods","pmids":["23007648"],"is_preprint":false},{"year":2012,"finding":"CDC20 is phosphorylated at six conserved residues (S50/T64/T68/T79/S114/S165) by CDK in Xenopus extracts. When threonine residues are phosphorylated, CDC20 binding to and activation of APC/C are inhibited. PP2A (active in mitosis) specifically dephosphorylates these threonine residues to activate APC/C. The 'activation domain' of CDC20 associates with APC/C subunits Apc6 and Apc8.","method":"In vitro kinase/phosphatase assays, Xenopus egg extracts, phospho-mutagenesis, co-immunoprecipitation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, phospho-mutagenesis, phosphatase specificity determined, multiple orthogonal methods","pmids":["22713866"],"is_preprint":false},{"year":2014,"finding":"APC/C-CDC20 ubiquitinates the pro-apoptotic BH3-only protein Bim, targeting it for proteasomal degradation. Cdc20 depletion sensitizes cells to apoptotic stimuli by stabilizing Bim. Tax viral oncoprotein elevates APC/C(CDC20) activity to reduce Bim levels and confer apoptotic resistance.","method":"siRNA screen, ubiquitination assay, co-immunoprecipitation, in vitro degradation assay","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — ubiquitination assay demonstrating Bim as APC/C(CDC20) substrate, siRNA screen, co-IP, functional rescue experiments","pmids":["24871945"],"is_preprint":false},{"year":2015,"finding":"Parkin (E3 ubiquitin ligase) interacts with CDC20 and CDH1 to mediate degradation of mitotic regulators independent of APC/C. Parkin is phosphorylated and activated by Plk1 during mitosis. Parkin deficiency causes overexpression of its substrates, mitotic defects, genomic instability, and tumorigenesis.","method":"Co-immunoprecipitation, ubiquitination assay, kinase assay, genetic knockout","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP, ubiquitination assay, kinase assay, in vivo knockout with phenotype, multiple orthogonal methods","pmids":["26387737"],"is_preprint":false},{"year":2016,"finding":"Bub1 directly phosphorylates CDC20, and also scaffolds Plk1-mediated phosphorylation of CDC20. Bub1-Plk1-dependent Cdc20 phosphorylation inhibits APC/C(CDC20) in vitro and is required for spindle checkpoint signalling in human cells. This phosphorylation is regulated by upstream checkpoint signals and is dispensable for MCC assembly. A phospho-mimicking CDC20 mutant can restore nocodazole-induced mitotic arrest in Mad2- or BubR1-depleted cells.","method":"In vitro kinase assay, APC/C ubiquitination assay, phospho-mutagenesis, RNAi in human cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay, in vitro APC/C inhibition assay, phospho-mutagenesis with in vivo validation, multiple orthogonal methods","pmids":["26912231"],"is_preprint":false},{"year":2016,"finding":"SPOP (Cullin3 adaptor) directly interacts with CDC20 via its degron and promotes CDC20 polyubiquitination and degradation. Cullin3 (but not Cullin1) specifically interacts with and degrades CDC20. Prostate cancer-derived SPOP mutants fail to bind CDC20 and promote its degradation, resulting in elevated CDC20.","method":"Co-immunoprecipitation, ubiquitination assay, half-life assay, MLN4924 pharmacological inhibition","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay, half-life measurement, single lab","pmids":["27780719"],"is_preprint":false},{"year":2016,"finding":"Cyclin A2-Cdk2 binds and phosphorylates CDC20 during interphase, inhibiting APC/C-CDC20 activity. Preventing CDC20 phosphorylation results in premature APC/C-CDC20 activation and destabilization of cyclin B1 and A2, lengthening G2 and slowing mitotic entry. Expressing non-degradable cyclin A2 (but not cyclin B1) restores mitotic entry.","method":"Co-immunoprecipitation, in vitro kinase assay, phospho-mutagenesis, cell synchronization","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay, phospho-mutagenesis, genetic rescue experiment, multiple orthogonal methods","pmids":["26960431"],"is_preprint":false},{"year":2017,"finding":"Kinetochore-localized PP1 dephosphorylates CDC20, directing it toward APC/C activation and promoting mitotic exit. Both APC/C activation and inhibition depend on CDC20 fluxing through the same kinetochore binding site; the microtubule attachment status controls the balance between these opposing CDC20 fates.","method":"Live imaging, kinase/phosphatase inhibitor experiments, RNAi in C. elegans and human cells","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional genetic and pharmacological dissection of dual CDC20 fate at kinetochores, multiple model systems","pmids":["28698300"],"is_preprint":false},{"year":2011,"finding":"CDC20 transcriptionally activates expression of the E2 ubiquitin-conjugating enzyme UbcH10 via its WD40 domain. CDC20 physically interacts with APC/C-CBP/p300 complex, and this complex is recruited to the UBCH10 promoter to drive transcription. This activity is cell cycle-specific.","method":"Reporter assay, co-immunoprecipitation, ChIP, WD40 domain mutagenesis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP of CDC20-CBP/p300 at UBCH10 promoter, domain mutagenesis, co-IP, single lab","pmids":["21454660"],"is_preprint":false},{"year":2010,"finding":"APC/C(CDC20) targets E2F1 for degradation in prometaphase. Ectopic expression of CDC20 reduces E2F1 protein levels; CDC20 knockdown stabilizes E2F1 and leads to its accumulation in prometaphase cells. Co-expression of DP1 with E2F1 blocks APC/C-induced E2F1 degradation.","method":"Co-expression experiments, siRNA knockdown, cell synchronization, ubiquitination assay","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CDC20 knockdown stabilizes substrate, rescue by DP1 co-expression, single lab","pmids":["20948288"],"is_preprint":false},{"year":2012,"finding":"RAP80 is polyubiquitinated and degraded by APC/C(CDC20) in mitosis (and by APC/C(CDH1) in G1). Knockdown of CDC20 blocks RAP80 degradation during mitosis. A conserved D-box in RAP80 is required for its ubiquitination and stability control by APC/C(CDC20).","method":"siRNA knockdown, ubiquitination assay, D-box mutagenesis, cell cycle synchronization","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown phenotype with substrate stabilization, D-box mutagenesis, in vitro ubiquitination, single lab","pmids":["22426463"],"is_preprint":false},{"year":2019,"finding":"CDC20 promotes degradation of Axin1 (core member of the β-catenin destruction complex) via its E3 ligase activity, reducing β-catenin phosphorylation and promoting β-catenin nuclear translocation and transcriptional activity in prostate cancer stem-like cells.","method":"siRNA knockdown, Western blot for downstream signaling, sphere formation and tumorigenicity assays","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — downstream pathway analysis after CDC20 knockdown, substrate identification by Western blot, single lab without direct ubiquitination assay","pmids":["30904606"],"is_preprint":false},{"year":2020,"finding":"APC/C(CDC20) binds to the D-box motif in PHD3 protein and promotes its polyubiquitination and degradation, thereby stabilizing HIF-1α and promoting VEGF secretion in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation, ubiquitination assay, CDC20 knockdown/pharmacological inhibition, PHD3 D-box mutagenesis","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay, D-box mutagenesis, but single lab","pmids":["33039559"],"is_preprint":false},{"year":2018,"finding":"CDC20 directly targets LC3 (a key autophagy regulator) for ubiquitination and proteasomal degradation, thereby inhibiting autophagy and promoting cardiac hypertrophy.","method":"Co-immunoprecipitation, ubiquitination assay, rAAV9-mediated cardiac overexpression/knockdown in vivo, in vitro cardiomyocyte assays","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay, in vivo cardiac model, single lab","pmids":["30613277"],"is_preprint":false},{"year":2021,"finding":"CDC20 specifically interacts with GSDME via its degron and promotes GSDME ubiquitination and proteasomal degradation in a degron-dependent manner, thereby suppressing pyroptosis in prostate cancer cells.","method":"Immunoprecipitation, ubiquitination assay, siRNA knockdown, cycloheximide chase assay, in vivo syngeneic mouse models","journal":"Experimental hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay, degron-dependency shown, in vivo validation, single lab","pmids":["37528490"],"is_preprint":false},{"year":2021,"finding":"CDC20 (via its WD40 domain) interacts with the DNA-binding domain of p65 (NF-κB subunit) and promotes APC11-dependent ubiquitination and degradation of p65 to promote osteogenic differentiation. Cdc20 conditional knockout mice display decreased bone formation.","method":"Co-immunoprecipitation, ubiquitination assay, domain mapping, conditional knockout mouse model","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP with domain mapping, ubiquitination assay, in vivo knockout with bone phenotype rescue, multiple orthogonal methods","pmids":["34382737"],"is_preprint":false},{"year":2021,"finding":"CDC20 assists its own catalytic incorporation into the mitotic checkpoint complex (MCC) as a substrate-assisted catalyst. Simultaneous docking on several sites of the catalytic kinetochore complex is required for CDC20 to access MAD2. The catalyst promotes MCC assembly through spatially and temporally coordinated conformational changes in both MAD2 and CDC20.","method":"Reconstituted SAC system, biochemical analysis with purified components, structural/conformational analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted SAC system with purified components, mechanistic dissection of conformational changes, rigorous biochemical characterization","pmids":["33384373"],"is_preprint":false},{"year":2021,"finding":"Kinetochore-catalyzed MAD2-CDC20 assembly occurs through a tripartite mechanism: localized delivery of MAD2 and CDC20 substrates plus two phosphorylation-dependent interactions that geometrically constrain their positions and prime CDC20 for MAD2 interaction.","method":"Reconstituted kinetochore system, live-cell probe for Mad2-Cdc20 assembly, epistasis with phospho-mutants","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted system, live-cell probe, phospho-mutagenesis, multiple orthogonal approaches","pmids":["33384372"],"is_preprint":false},{"year":2020,"finding":"PP1 removes specific inhibitory phosphorylation in the N-terminus of CDC20 to promote APC/C(CDC20)-dependent cyclin B destruction at anaphase onset. Depletion or chemical inhibition of PP1 stabilizes cyclin B and delays metaphase-to-anaphase transition. CDC206A (CDK1 phosphorylation-defective) mutant cells rapidly destroy cyclin B and enter anaphase without PP1 activity.","method":"PP1 depletion/inhibition, phospho-mutagenesis (CDC206A), cell biology, cyclin B stability assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — PP1 inhibition/depletion combined with phospho-mutagenesis rescue, clear mechanistic dissection, single lab but multiple orthogonal methods","pmids":["32755477"],"is_preprint":false},{"year":2019,"finding":"PP2A-B56 directly binds the disordered Apc1-loop500 domain of APC/C and stimulates CDC20 loading onto APC/C by dephosphorylating CDC20. Mutations in Apc1-loop500 abolishing B56 binding decrease CDC20 loading and APC/C-dependent ubiquitylation. A non-phosphorylatable CDC20 mutant bypasses the need for PP2A-B56.","method":"APC/C reconstitution in Xenopus egg extracts, mutagenesis, co-immunoprecipitation, in vitro ubiquitylation assay","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted APC/C system, mutagenesis, phosphatase specificity determined, multiple orthogonal methods","pmids":["31825153"],"is_preprint":false},{"year":2022,"finding":"Mps1-phosphorylated Mad1 CTD creates a phosphorylation-specific interaction with CDC20. Together with Mps1-phosphorylation of Bub1, this generates a tripartite assembly of Bub1 and CDC20 onto the C-terminal domain of Mad1, positioning the Mad2-interacting motif (MIM) of CDC20 near open-Mad2 to catalyse formation of C-MAD2:CDC20.","method":"Structural analysis (NMR, cross-linking MS), biochemical binding assays, mutagenesis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural data combined with biochemical binding assays and mutagenesis, multiple orthogonal methods","pmids":["36289199"],"is_preprint":false},{"year":2023,"finding":"Human cells express conserved alternative CDC20 translational isoforms initiated at downstream AUGs (e.g., Met43). The truncated Met43 isoform lacks key N-terminal SAC inhibitory binding sites and is resistant to SAC-mediated inhibition, promoting mitotic exit even in the presence of mitotic perturbations. Differential turnover of full-length vs. truncated isoforms during prolonged arrest creates a molecular timer controlling mitotic slippage duration.","method":"Isoform-specific mutagenesis, ribosome profiling, cell synchronization, SAC assays, CRISPR engineering","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — engineered CDC20 isoform variants, functional SAC assays, CRISPR-based isoform manipulation, multiple orthogonal methods","pmids":["37100900"],"is_preprint":false},{"year":2023,"finding":"BUB-1-bound PLK-1 phosphorylates the ABBA motif of BUB-1 to promote BUB-1-CDC-20 interaction and CDC-20 kinetochore recruitment. This PLK-1 kinase activity at kinetochores is required for CDC-20 localization to kinetochores and timely mitotic progression in C. elegans embryos, functioning in a checkpoint-independent manner.","method":"C. elegans genetics, live imaging, phospho-mutagenesis, kinase inhibitor experiments","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic and pharmacological dissection with phospho-mutagenesis, live imaging, C. elegans ortholog study with conserved mechanism","pmids":["37137308"],"is_preprint":false},{"year":2018,"finding":"PPM1K (mitochondrial phosphatase regulating BCAA catabolism) maintains MEIS1 and p21 levels by decreasing CDC20-mediated ubiquitination and degradation. PPM1K deficiency leads to increased CDC20-dependent degradation of MEIS1 and p21, reducing HSC glycolysis and quiescence.","method":"Co-immunoprecipitation, ubiquitination assay, genetic knockout in mice, fluorescent BCAA sensor","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay, in vivo knockout, single lab","pmids":["29719258"],"is_preprint":false},{"year":2015,"finding":"CDC20-APC drives invasiveness and self-renewal in glioblastoma stem-like cells (GSCs) through degradation of the pluripotency transcription factor SOX2.","method":"shRNA knockdown, overexpression, orthotopic xenograft, Western blot for SOX2 levels","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — knockdown phenotype with substrate identification, in vivo tumor model, single lab","pmids":["26074073"],"is_preprint":false},{"year":2015,"finding":"CDC20 maintains glioblastoma tumor initiating cells (TICs) through APC/C-dependent degradation of p21(CIP1/WAF1). CDC20 disruption stabilizes p21, repressing CDC25C, c-Myc, and Survivin. FOXM1 transcriptionally controls CDC20 expression in TICs.","method":"RNAi knockdown, ubiquitination assay, ChIP for FOXM1 at CDC20 promoter, chromatin analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay, ChIP, knockdown phenotype, single lab","pmids":["25938542"],"is_preprint":false},{"year":2020,"finding":"CDC20 directly interacts with Mcl-1 (anti-apoptotic Bcl-2 family member), and this interaction is required for Mcl-1 stability. Knockdown of CDC20 suppresses Mcl-1 expression, inhibits p-Chk1, impairs Rad51-mediated DNA repair, and induces apoptosis in colorectal cancer cells.","method":"Co-immunoprecipitation, GST pulldown assay, siRNA knockdown, in vivo radiosensitization study","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and GST pulldown confirming direct interaction, functional consequence of knockdown, single lab","pmids":["32932732"],"is_preprint":false},{"year":2009,"finding":"Cdc20 and PC-PLC co-immunoprecipitate and co-localize in the perinuclear endoplasmic reticulum (JUNQ compartment) in rat hepatoma cells. Cdc20 overexpression alters PC-PLC subcellular localization and causes its degradation via the ubiquitin-proteasome pathway, demonstrating APC/C(Cdc20) targets PC-PLC.","method":"Co-immunoprecipitation, confocal microscopy co-localization, overexpression, proteasome inhibitor experiment","journal":"Journal of cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP and co-localization, single lab, single method for ubiquitin-mediated degradation, non-canonical substrate","pmids":["19347873"],"is_preprint":false},{"year":2006,"finding":"A second Mad2-binding domain on CDC20 was identified in amino acids 342-355 within the WD repeat region. An intervening region between this domain and the previously known N-terminal domain (aa 111-150) interferes with Mad2 binding when either domain is present alone. Optimal Mad2 binding requires coordination of three domains. A polyhistidine motif adjacent to the second binding domain may maintain CDC20 conformation for Mad2 binding.","method":"Co-immunoprecipitation and co-localization with CDC20 deletion mutants, peptide inhibition assay","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — systematic deletion mutant analysis with co-IP and co-localization, multiple mutants tested, single lab","pmids":["16497171"],"is_preprint":false},{"year":2021,"finding":"Cdc20 downregulation or APC/C inhibition induces premature senescence in normal lung fibroblasts through GSK-3β-mediated phosphorylation and downregulation of securin. In NSCLC cells (which bypass senescence), the same pathway induces apoptosis through securin downregulation.","method":"siRNA knockdown, APC/C pharmacological inhibitor, GSK-3β inhibitor rescue, Western blot for securin phosphorylation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway dissection via multiple inhibitors and knockdown, cell-type-specific phenotype, single lab","pmids":["35988650"],"is_preprint":false},{"year":2010,"finding":"In Drosophila, BubR1 (but not Mad2) is required for CDC20 recruitment to kinetochores. BubR1 and Mad2 can bind CDC20 independently, and their interactions are enhanced during mitotic arrest. This demonstrates that BubR1 provides the primary kinetochore-CDC20 recruitment mechanism in flies.","method":"RNAi in Drosophila S2 cells and syncytial embryos, live imaging, co-immunoprecipitation","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi dissection with co-IP, live imaging, Drosophila ortholog study with clear mechanistic distinction from vertebrates","pmids":["20421417"],"is_preprint":false},{"year":2023,"finding":"PRMT6 maintains CDC20 transcription via H3R2me2a histone methylation at the CDC20 promoter. CDC20 in turn interacts with CDKN1B (p27) and destabilizes it via ubiquitin-mediated degradation, promoting GBM cell proliferation.","method":"ChIP-qPCR for PRMT6/H3R2me2a at CDC20 promoter, co-immunoprecipitation for CDC20-CDKN1B, ubiquitination assay, rescue experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP evidence for PRMT6 regulation of CDC20 transcription, co-IP and ubiquitination for CDC20-CDKN1B, single lab","pmids":["36792756"],"is_preprint":false}],"current_model":"CDC20 is an essential WD40-repeat co-activator of the APC/C E3 ubiquitin ligase that directly recognizes substrates (cyclin B, securin, cyclin A, Bim, E2F1, RAP80, PHD3, LC3, p65, GSDME, and others) via its N-terminus and WD40 domain, activates APC/C to drive anaphase onset and mitotic exit, and is itself regulated by a cycle of CDK1-mediated phosphorylation (which inhibits APC/C binding) countered by PP1/PP2A-B56-mediated dephosphorylation (which promotes APC/C binding), by MAD2/BubR1-containing MCC formation at unattached kinetochores that sequesters CDC20 away from APC/C, by Bub1-Plk1-mediated phosphorylation providing an MCC-independent APC/C inhibitory mechanism, and by APC15-facilitated autoubiquitylation that drives MCC disassembly; beyond mitosis, CDC20-APC also controls dendrite morphogenesis, presynaptic differentiation, osteogenesis (via p65 degradation), and autophagy (via LC3 degradation) in postmitotic cells."},"narrative":{"mechanistic_narrative":"CDC20 is the essential mitotic co-activator of the anaphase-promoting complex/cyclosome (APC/C), a WD40-repeat protein that confers substrate specificity on this E3 ubiquitin ligase to drive the metaphase-to-anaphase transition and mitotic exit [PMID:9628895, PMID:11562349]. It exists in distinct cell-cycle forms — inactive MAD2-CDC20-APC at metaphase and active CDC20-APC at anaphase — and recognizes substrates directly through its N-terminus independently of the APC/C core, with the N-terminus serving as the specificity determinant [PMID:9637688, PMID:11562349]. CDC20 abundance and activity are tightly periodic, peaking at M phase and falling at the M/G1 transition through proteasomal degradation and APC/C-dependent autoubiquitylation in cis [PMID:9353311, PMID:22079111]. Its activity is gated by a phosphorylation switch: CDK1/cyclin A-Cdk2 phosphorylation of conserved N-terminal threonines inhibits APC/C binding, while mitotic PP2A-B56 (acting at the Apc1-loop500) and kinetochore PP1 dephosphorylate CDC20 to license APC/C loading and substrate destruction including cyclin B [PMID:22713866, PMID:26960431, PMID:32755477, PMID:31825153]. The spindle assembly checkpoint restrains CDC20 by two routes — MAD2 binds a site required for APC/C association and competes with the APC/C for CDC20, and Bub1-scaffolded Plk1 phosphorylation provides an MCC-independent inhibitory mechanism [PMID:23007648, PMID:26912231]; kinetochores catalyze MAD2-CDC20 (MCC) assembly through phosphorylation-dependent, geometrically constrained delivery of MAD2 and CDC20, with CDC20 itself acting as a substrate-assisted catalyst of its own incorporation [PMID:33384373, PMID:33384372, PMID:36289199]. APC/C-CDC20 substrates extend across mitotic regulators (cyclin A, securin, E2F1, RAP80) and, in postmitotic and disease contexts, to Bim, p65, GSDME, LC3, p21, and SOX2, linking CDC20 to apoptosis, autophagy, osteogenic differentiation, neuronal dendrite morphogenesis, and tumor cell self-renewal [PMID:18471975, PMID:19167333, PMID:19900895, PMID:20941357, PMID:24871945, PMID:20948288, PMID:22426463, PMID:34382737]. CDC20 levels are themselves set transcriptionally, being repressed by p53 under genotoxic stress and activated by FOXM1 and PRMT6, and post-translationally controlled by SPOP-Cullin3 and Parkin [PMID:17873905, PMID:26387737, PMID:27780719, PMID:25938542, PMID:36792756].","teleology":[{"year":1994,"claim":"Established that the mammalian CDC20 ortholog p55CDC is a cell-cycle protein that associates, via its WD repeats, with a kinase activity peaking at M phase — the first hint that it operates within a mitotic regulatory complex.","evidence":"Immunoprecipitation, kinase assay, and immunolocalization in cycling mammalian cells","pmids":["7513050"],"confidence":"Medium","gaps":["Associated kinase not identified","No demonstration of APC/C function or substrate"]},{"year":1997,"claim":"Showed CDC20 protein is cell-cycle periodic and that its destruction at M/G1 requires the 26S proteasome, tying CDC20 turnover to mitotic exit.","evidence":"Cell synchronization with proteasome inhibition and immunolocalization","pmids":["9353311"],"confidence":"Medium","gaps":["Ubiquitin ligase responsible not defined","Mechanism of degradation (autoubiquitylation vs other) not resolved"]},{"year":1998,"claim":"Defined CDC20 as the APC/C activator whose checkpoint inhibition is mediated by MAD2, and established it as the physical bridge linking MAD2 to APC/C subunits — placing CDC20 at the heart of the spindle checkpoint.","evidence":"In vitro reconstitution with recombinant proteins, Xenopus microinjection, reciprocal co-IP of MAD2/CDC20/APC components, live imaging","pmids":["9637688","9628895","9736712"],"confidence":"High","gaps":["Structural basis of MAD2-CDC20 binding undefined","How CDC20 selects substrates not yet shown"]},{"year":2001,"claim":"Resolved how CDC20 confers substrate specificity, showing its N-terminus binds APC/C substrates directly and independently of the APC/C core.","evidence":"In vitro binding, chimeric proteins, and ubiquitination assays without APC/C","pmids":["11562349"],"confidence":"High","gaps":["Full repertoire of recognition motifs (D-box vs KEN) not enumerated here","Role of WD40 domain in substrate binding addressed only later"]},{"year":2003,"claim":"Established that CDK/MAPK phosphorylation of CDC20 does not block APC/C activation per se but controls its affinity for checkpoint proteins, defining CDC20 phosphorylation as the substrate of checkpoint control.","evidence":"In vitro kinase and APC/C assays with phospho-site mutagenesis in Xenopus extracts","pmids":["12855955"],"confidence":"High","gaps":["Counteracting phosphatase not identified at this stage","Precise residues governing each checkpoint-protein interaction not fully mapped"]},{"year":2008,"claim":"Explained how cyclin A is degraded despite an active checkpoint, showing CDC20 binds cyclin A with little associated Mad2 to permit checkpoint-independent destruction.","evidence":"Reciprocal co-IP, in vitro ubiquitination, and RNAi with synchronization","pmids":["18471975"],"confidence":"High","gaps":["Structural basis for Cks-dependent recognition unresolved","Why cyclin A escapes checkpoint while cyclin B does not only partially explained"]},{"year":2009,"claim":"Extended CDC20-APC function beyond mitosis into postmitotic neurons, showing centrosomal CDC20-APC controls dendrite morphogenesis and degrades NeuroD2 to drive presynaptic differentiation.","evidence":"In vivo knockdown in rat cerebellum, live imaging, ubiquitination assays, and genetic epistasis","pmids":["19167333","19900895"],"confidence":"High","gaps":["How CDC20-APC is activated in postmitotic cells lacking cell-cycle cues unclear","Full neuronal substrate set undefined"]},{"year":2012,"claim":"Dissected the two-pronged regulation of CDC20: CDK phosphorylation of N-terminal threonines blocks APC/C binding while mitotic PP2A removes them, and MAD2 directly competes with APC/C for CDC20 — defining the phosphorylation switch and a non-pseudosubstrate checkpoint mechanism.","evidence":"In vitro kinase/phosphatase assays, Xenopus extracts, competition binding, and in vivo checkpoint mutagenesis","pmids":["22713866","23007648"],"confidence":"High","gaps":["Identity of the in vivo kinetochore phosphatase not yet pinned","Coordination between MAD2 competition and phospho-control not integrated"]},{"year":2012,"claim":"Identified APC15 as the subunit enabling APC/C(MCC)-dependent CDC20 autoubiquitylation that drives MCC disassembly, providing the mechanism for checkpoint silencing.","evidence":"RNAi depletion and in vitro ubiquitylation with reconstituted human APC/C","pmids":["22079111","23007861"],"confidence":"High","gaps":["How substrate levels tune the autoubiquitylation/disassembly balance not fully quantified","Structural arrangement at the MCC-binding site addressed only later"]},{"year":2016,"claim":"Revealed an MCC-independent checkpoint mechanism in which Bub1 directly and Plk1-scaffolded phosphorylation of CDC20 inhibits APC/C(CDC20), and showed interphase cyclin A2-Cdk2 phosphorylation of CDC20 sets the timing of mitotic entry.","evidence":"In vitro kinase and APC/C inhibition assays, phospho-mutagenesis with RNAi in human cells, and genetic rescue with non-degradable cyclin A2","pmids":["26912231","26960431"],"confidence":"High","gaps":["Relative contribution of MCC vs Bub1-Plk1 phosphorylation in vivo not quantified","Crosstalk between interphase and mitotic phospho-control unresolved"]},{"year":2017,"claim":"Showed that APC/C activation and inhibition both depend on CDC20 fluxing through a single kinetochore site, with PP1 dephosphorylation directing CDC20 toward APC/C activation and microtubule attachment status setting the balance.","evidence":"Live imaging with kinase/phosphatase inhibitors and RNAi in C. elegans and human cells","pmids":["28698300"],"confidence":"High","gaps":["Molecular determinant that switches CDC20 fate at the shared site not fully defined"]},{"year":2020,"claim":"Mapped the phosphatases that license CDC20-APC/C loading, showing PP2A-B56 binds the Apc1-loop500 to dephosphorylate CDC20 and PP1 removes N-terminal inhibitory phosphorylation to permit cyclin B destruction at anaphase.","evidence":"Reconstituted APC/C in Xenopus extracts, PP1 depletion/inhibition, and CDC20 phospho-mutant rescue","pmids":["31825153","32755477"],"confidence":"High","gaps":["Spatial coordination of PP1 vs PP2A-B56 action on CDC20 not integrated","How phosphatase activity is locally controlled at kinetochores unresolved"]},{"year":2021,"claim":"Provided the mechanism of kinetochore-catalyzed MCC assembly, showing CDC20 is a substrate-assisted catalyst whose own multi-site docking and phosphorylation-dependent geometric constraints prime MAD2 capture.","evidence":"Reconstituted SAC/kinetochore systems with purified components, conformational analysis, live-cell probes, and phospho-mutagenesis","pmids":["33384373","33384372"],"confidence":"High","gaps":["Full structural intermediate of the assembly reaction not solved","Kinetics of catalysis in living cells only inferred"]},{"year":2021,"claim":"Broadened CDC20 substrate biology into differentiation and cell death, establishing WD40-mediated degradation of NF-kB p65 in osteogenesis with an in vivo bone phenotype.","evidence":"Co-IP with domain mapping, APC11-dependent ubiquitination assays, and conditional knockout mice","pmids":["34382737"],"confidence":"High","gaps":["How CDC20-APC is engaged in non-dividing osteoblasts not detailed","Relationship to mitotic CDC20 regulation unclear"]},{"year":2023,"claim":"Uncovered an additional layer of CDC20 control: alternative translational isoforms (e.g. Met43) lacking N-terminal SAC sites resist checkpoint inhibition and act as a molecular timer for mitotic slippage, and a conserved Bub1-Plk1/ABBA pathway recruits CDC20 to kinetochores independent of the checkpoint.","evidence":"Ribosome profiling, isoform-specific and CRISPR engineering with SAC assays; C. elegans genetics and live imaging with phospho-mutagenesis","pmids":["37100900","37137308"],"confidence":"High","gaps":["Physiological triggers selecting isoform usage not defined","How checkpoint-independent kinetochore recruitment integrates with MCC formation unresolved"]},{"year":null,"claim":"How CDC20's many non-mitotic substrates and its transcriptional/post-translational regulators are coordinated across distinct cell types, and the structural basis for switching between substrate ubiquitylation and self-inhibition, remain to be integrated.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking mitotic vs postmitotic CDC20 activation","Many cancer-context substrates rest on single-lab Co-IP/knockdown without reconstitution","Direct E3 ligase mechanism for several non-canonical substrates not biochemically resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5,8,20,28,30,33]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,5,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,5]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[26]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,5,8,16,24,36]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,8,16,17,20,33]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[20,32,47]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[31]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,10,33]}],"complexes":["APC/C","Mitotic checkpoint complex (MCC)"],"partners":["MAD2","BUBR1","CDC27","BUB1","AURKA","PP2A-B56","PP1","MAD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q12834","full_name":"Cell division cycle protein 20 homolog","aliases":["p55CDC"],"length_aa":499,"mass_kda":54.7,"function":"Substrate-specific adapter of the anaphase promoting complex/cyclosome (APC/C) complex that confers substrate specificity by binding to substrates and targeting them to the APC/C complex for ubiquitination and degradation (PubMed:9734353, PubMed:27030811, PubMed:29343641). Recognizes and binds the destruction box (D box) on protein substrates (PubMed:29343641). Involved in the metaphase/anaphase transition of cell cycle (PubMed:32666501). Is regulated by MAD2L1: in metaphase the MAD2L1-CDC20-APC/C ternary complex is inactive and in anaphase the CDC20-APC/C binary complex is active in degrading substrates (PubMed:9811605, PubMed:9637688). The CDC20-APC/C complex positively regulates the formation of synaptic vesicle clustering at active zone to the presynaptic membrane in postmitotic neurons (By similarity). CDC20-APC/C-induced degradation of NEUROD2 induces presynaptic differentiation (By similarity). The CDC20-APC/C complex promotes proper dilation formation and radial migration by degrading CCDC41 (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Chromosome, centromere, kinetochore; Cytoplasm, cytoskeleton, spindle pole","url":"https://www.uniprot.org/uniprotkb/Q12834/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CDC20","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000117399","cell_line_id":"CID000228","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"cytoplasmic","grade":1},{"compartment":"nuclear_punctae","grade":1}],"interactors":[{"gene":"ANAPC16","stoichiometry":4.0},{"gene":"BUB1B","stoichiometry":4.0},{"gene":"CDC23","stoichiometry":4.0},{"gene":"ANAPC2","stoichiometry":0.2},{"gene":"ANAPC4","stoichiometry":0.2},{"gene":"CDC16","stoichiometry":0.2},{"gene":"PRDX1","stoichiometry":0.2},{"gene":"CDC26","stoichiometry":0.2},{"gene":"CDC27","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000228","total_profiled":1310},"omim":[{"mim_id":"620276","title":"OOCYTE/ZYGOTE/EMBRYO MATURATION ARREST 14; OZEMA14","url":"https://www.omim.org/entry/620276"},{"mim_id":"618136","title":"MAD2L1-BINDING PROTEIN; MAD2L1BP","url":"https://www.omim.org/entry/618136"},{"mim_id":"617621","title":"PAX3- AND PAX7-BINDING PROTEIN 1; PAXBP1","url":"https://www.omim.org/entry/617621"},{"mim_id":"617611","title":"PICALM-INTERACTING MITOTIC REGULATOR; PIMREG","url":"https://www.omim.org/entry/617611"},{"mim_id":"615774","title":"OOCYTE/ZYGOTE/EMBRYO MATURATION ARREST 1; OZEMA1","url":"https://www.omim.org/entry/615774"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":50.8},{"tissue":"lymphoid tissue","ntpm":49.0},{"tissue":"testis","ntpm":46.8}],"url":"https://www.proteinatlas.org/search/CDC20"},"hgnc":{"alias_symbol":["p55CDC","CDC20A"],"prev_symbol":[]},"alphafold":{"accession":"Q12834","domains":[{"cath_id":"2.130.10.10","chopping":"186-306","consensus_level":"medium","plddt":98.4012,"start":186,"end":306},{"cath_id":"2.130.10.10","chopping":"314-473","consensus_level":"medium","plddt":97.8797,"start":314,"end":473}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12834","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12834-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12834-F1-predicted_aligned_error_v6.png","plddt_mean":84.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDC20","jax_strain_url":"https://www.jax.org/strain/search?query=CDC20"},"sequence":{"accession":"Q12834","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12834.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12834/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12834"}},"corpus_meta":[{"pmid":"9637688","id":"PMC_9637688","title":"The 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Only the MAD2 tetramer (not monomer) inhibits APC activation, demonstrating that MAD2 binding alone is insufficient for inhibition and that MAD2 oligomeric state matters. Three forms of mitotic APC were identified: inactive MAD2-CDC20-APC at metaphase, active CDC20-APC at anaphase, and CDH1-APC in G1.\",\n      \"method\": \"In vitro reconstitution with recombinant proteins, Xenopus embryo microinjection, immunoprecipitation\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with recombinant proteins, functional validation in Xenopus embryos, multiple orthogonal methods\",\n      \"pmids\": [\"9637688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Mammalian p55CDC (CDC20) localizes to kinetochores from late prophase to telophase, to spindle microtubules and poles, and to the cytoplasm. In M-phase (but not interphase) extracts, p55CDC co-immunoprecipitates with APC components CDC27 and CDC16, and with MAD2. p55CDC is required for the association of MAD2 with CDC27 and CDC16, acting as a bridge between MAD2 and the APC/C.\",\n      \"method\": \"Immunofluorescence, GFP chimera live imaging, co-immunoprecipitation from HeLa cell extracts, antibody microinjection\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, direct localization by live imaging and IF, functional antibody injection, multiple orthogonal methods\",\n      \"pmids\": [\"9628895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"p55CDC (CDC20) is expressed in cycling mammalian cells and is phosphorylated during cell division. Immunoprecipitates of p55CDC contain associated kinase activity that fluctuates during the cell cycle (peaking at M phase), indicating p55CDC associates with a cell cycle-regulated kinase complex via its seven WD repeats.\",\n      \"method\": \"Immunoprecipitation, kinase assay, antisense transfection, immunolocalization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, kinase co-IP without identification of the kinase, multiple methods but indirect\",\n      \"pmids\": [\"7513050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"p55CDC protein levels are highest at M phase and lowest in G1. Its degradation at the M/G1 transition is mediated by the 26S proteasome (inhibition of the proteasome prevents both mitotic exit and loss of p55CDC). Dynamic changes in p55CDC localization occur as cells transit mitosis.\",\n      \"method\": \"Cell synchronization, proteasome inhibitor treatment, immunolocalization, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteasome inhibitor functional experiment with localization data, single lab\",\n      \"pmids\": [\"9353311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"MAD2 associates with the APC component CDC27 transiently during early normal mitosis (not only upon checkpoint activation), and this association requires p55CDC (CDC20), forming a MAD2/p55CDC/CDC27 ternary complex. A MAD2/CDC27 complex that forms independently of p55CDC was also detected.\",\n      \"method\": \"Co-immunoprecipitation from mammalian cells at different cell cycle stages\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP across multiple cell cycle stages, single lab, single primary method\",\n      \"pmids\": [\"9736712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CDC20 (and CDH1) directly bind APC/C substrates via their N-termini, independent of APC/C. The N-terminus of CDC20 confers substrate specificity. Active chimeras swapping N-termini demonstrate that the N-terminus is the specificity determinant for substrate recognition.\",\n      \"method\": \"In vitro binding assays, chimeric protein construction, ubiquitination assays in the absence of APC/C\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis/chimeras, direct substrate binding demonstrated independent of APC\",\n      \"pmids\": [\"11562349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Xenopus CDC20 is phosphorylated at Ser50, Thr64, Thr68, and Thr79 during mitosis; MAPK contributes to phosphorylation at Thr64 or Thr68. Phosphorylation-deficient CDC20 mutants activate APC/C normally but fail to respond to spindle checkpoint signals due to reduced affinity for spindle checkpoint proteins (BubR1, Bub3, Mad2). Thus, the spindle checkpoint arrests cells by inhibiting fully-phosphorylated CDC20.\",\n      \"method\": \"In vitro kinase assays, Xenopus egg extract APC/C ubiquitination assays, phospho-site mutagenesis, checkpoint binding assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, site-directed mutagenesis, functional checkpoint assays in Xenopus extracts\",\n      \"pmids\": [\"12855955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In budding yeast, the PKA pathway supports Chk1 in restraining anaphase by phosphorylating Cdc20 on PKA consensus sites after DNA damage. This phosphorylation requires Mec1 (ATR ortholog) and PKA catalytic subunits Tpk1/Tpk2. Phosphorylation-defective Cdc20 mutants accelerate securin and Clb2 destruction and allow Cdc20 to interact with Clb2 under checkpoint conditions.\",\n      \"method\": \"Genetic epistasis, phospho-site mutagenesis, in vivo degradation assays, co-immunoprecipitation in yeast\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple mutants, phospho-mutagenesis, co-IP, yeast ortholog study\",\n      \"pmids\": [\"14743219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CDC20 is rate-limiting for cyclin A destruction and binds cyclin A efficiently before and during mitosis. The cyclin A-CDC20 complex has little associated Mad2, enabling spindle-checkpoint-independent cyclin A degradation. Cks protein binding to the cyclin A complex is additionally required for its checkpoint-independent degradation by APC/C-CDC20.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assays, RNA interference, cell synchronization\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, in vitro ubiquitination, RNAi phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"18471975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CDC20-APC plays an essential role in dendrite morphogenesis in postmitotic neurons. CDC20 is enriched at the centrosome in neurons, and centrosomal localization is critical for this function. HDAC6 promotes polyubiquitination of CDC20, stimulates centrosomal CDC20-APC activity, and drives dendrite differentiation.\",\n      \"method\": \"Knockdown in cerebellar slices and in vivo in rats, live imaging for centrosomal localization, ubiquitination assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockdown with specific phenotype, centrosomal localization tied to function, ubiquitination assay, multiple orthogonal methods\",\n      \"pmids\": [\"19167333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CDC20-APC triggers degradation of the transcription factor NeuroD2 to promote presynaptic differentiation in postmitotic neurons. NeuroD2's target gene Complexin II mediates its suppression of presynaptic differentiation.\",\n      \"method\": \"Knockdown in primary neurons and rat cerebellar cortex in vivo, ubiquitination assays, genetic epistasis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockdown, identification of substrate NeuroD2, epistasis with Complexin II, multiple orthogonal methods\",\n      \"pmids\": [\"19900895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CDC20 associates with the kinase Aurora2/Aik in HeLa cells. CDC20-associated MBP kinase activity peaks in early M phase (embryonic cells) or G2 phase (somatic cells). The association suggests that Aurora2/Aik carries out or regulates some CDC20 function.\",\n      \"method\": \"Co-immunoprecipitation from HeLa cells, kinase assay with MBP substrate\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP identifying Aurora2/Aik as CDC20-associated kinase, kinase assay, single lab\",\n      \"pmids\": [\"10377410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CDC20 (p55CDC) directly interacts with BUBR1 as shown by yeast two-hybrid, GST pulldown, and co-immunoprecipitation. BUBR1 phosphorylates p55CDC in vitro, and this phosphorylation correlates with spindle checkpoint activation. Spindle checkpoint activation by nocodazole enhances the p55CDC-BUBR1 association.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation from HeLa cells, in vitro kinase assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three independent binding methods (Y2H, GST pulldown, co-IP), in vitro kinase assay, functional correlation\",\n      \"pmids\": [\"11030144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"p53 transcriptionally represses CDC20 expression through binding to a consensus p53-binding site in the CDC20 promoter and through CDE/CHR elements. This repression occurs in response to genotoxic stress in a p53- and p21-dependent manner. siRNA-mediated silencing of p53 induces CDC20 expression in normal human dermal fibroblasts.\",\n      \"method\": \"Reporter assays, ChIP, siRNA knockdown, expression analysis after genotoxic stress\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct p53 binding to CDC20 promoter, functional reporter assay, single lab\",\n      \"pmids\": [\"17873905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"p53 binds directly to a consensus site in the CDC20 promoter and causes chromatin remodeling to repress CDC20 transcription. p53 also downregulates CDC20 through CDE/CHR elements in a p21-independent manner under p53-overexpression conditions. The CCAAT elements in the CDC20 promoter are not used by p53 for repression.\",\n      \"method\": \"ChIP, promoter reporter assay, chromatin remodeling analysis, p53 binding site mutagenesis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP evidence of p53-promoter binding, chromatin remodeling, single lab\",\n      \"pmids\": [\"19273532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cdc20 is critical for meiosis I in female mice. Cdc20 hypomorphic females produce aneuploid gametes due to chromosome lagging and misalignment during meiosis I. Cyclin B1, cyclin A2, and securin are inefficiently degraded in metaphase I, and anaphase I onset is markedly delayed, demonstrating Cdc20's role in APC/C activation during female meiosis.\",\n      \"method\": \"Hypomorphic mouse model, chromosome analysis, immunostaining, live oocyte imaging\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model, multiple substrates examined, direct meiotic phenotype with mechanistic substrate analysis\",\n      \"pmids\": [\"20941357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CDC20 undergoes APC/C-dependent autoubiquitination in cis (intramolecular mechanism) while bound to its activator-binding site on the APC/C core, independent of Cdc20's C-box. This cell-cycle-regulated mechanism contributes to the decline of CDC20 levels after anaphase. High substrate levels in vitro reduce Cdc20 autoubiquitination.\",\n      \"method\": \"In vitro ubiquitination assays, cell cycle synchronization, mutagenesis\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of autoubiquitination, mutagenesis distinguishing in cis from in trans mechanism\",\n      \"pmids\": [\"22079111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"APC15 is required for APC/C(MCC)-dependent CDC20 autoubiquitylation and degradation, and for timely anaphase initiation. APC15 is located near the APC/C MCC-binding site and is dispensable for substrate ubiquitylation by APC/C(CDC20) or APC/C(CDH1). CDC20 autoubiquitylation promotes MCC disassembly.\",\n      \"method\": \"RNAi depletion, in vitro ubiquitylation assays with recombinant human APC/C, cell biology\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted human APC/C system, RNAi phenotype, multiple orthogonal methods identifying APC15's specific role\",\n      \"pmids\": [\"23007861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mad2 inhibits CDC20 by binding directly to a site required for CDC20 to bind the APC/C. Mad2 and the APC/C compete for CDC20 in vitro, and a CDC20 mutant that does not bind stably to Mad2 abrogates the SAC in vivo. This reveals a second mechanism by which SAC inhibits APC/C (beyond pseudosubstrate inhibition).\",\n      \"method\": \"In vitro competition binding assay, mutagenesis, in vivo checkpoint assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro competition assay plus in vivo mutagenesis validating functional consequence, multiple orthogonal methods\",\n      \"pmids\": [\"23007648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CDC20 is phosphorylated at six conserved residues (S50/T64/T68/T79/S114/S165) by CDK in Xenopus extracts. When threonine residues are phosphorylated, CDC20 binding to and activation of APC/C are inhibited. PP2A (active in mitosis) specifically dephosphorylates these threonine residues to activate APC/C. The 'activation domain' of CDC20 associates with APC/C subunits Apc6 and Apc8.\",\n      \"method\": \"In vitro kinase/phosphatase assays, Xenopus egg extracts, phospho-mutagenesis, co-immunoprecipitation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, phospho-mutagenesis, phosphatase specificity determined, multiple orthogonal methods\",\n      \"pmids\": [\"22713866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"APC/C-CDC20 ubiquitinates the pro-apoptotic BH3-only protein Bim, targeting it for proteasomal degradation. Cdc20 depletion sensitizes cells to apoptotic stimuli by stabilizing Bim. Tax viral oncoprotein elevates APC/C(CDC20) activity to reduce Bim levels and confer apoptotic resistance.\",\n      \"method\": \"siRNA screen, ubiquitination assay, co-immunoprecipitation, in vitro degradation assay\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ubiquitination assay demonstrating Bim as APC/C(CDC20) substrate, siRNA screen, co-IP, functional rescue experiments\",\n      \"pmids\": [\"24871945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Parkin (E3 ubiquitin ligase) interacts with CDC20 and CDH1 to mediate degradation of mitotic regulators independent of APC/C. Parkin is phosphorylated and activated by Plk1 during mitosis. Parkin deficiency causes overexpression of its substrates, mitotic defects, genomic instability, and tumorigenesis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, kinase assay, genetic knockout\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP, ubiquitination assay, kinase assay, in vivo knockout with phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"26387737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Bub1 directly phosphorylates CDC20, and also scaffolds Plk1-mediated phosphorylation of CDC20. Bub1-Plk1-dependent Cdc20 phosphorylation inhibits APC/C(CDC20) in vitro and is required for spindle checkpoint signalling in human cells. This phosphorylation is regulated by upstream checkpoint signals and is dispensable for MCC assembly. A phospho-mimicking CDC20 mutant can restore nocodazole-induced mitotic arrest in Mad2- or BubR1-depleted cells.\",\n      \"method\": \"In vitro kinase assay, APC/C ubiquitination assay, phospho-mutagenesis, RNAi in human cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay, in vitro APC/C inhibition assay, phospho-mutagenesis with in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"26912231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SPOP (Cullin3 adaptor) directly interacts with CDC20 via its degron and promotes CDC20 polyubiquitination and degradation. Cullin3 (but not Cullin1) specifically interacts with and degrades CDC20. Prostate cancer-derived SPOP mutants fail to bind CDC20 and promote its degradation, resulting in elevated CDC20.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, half-life assay, MLN4924 pharmacological inhibition\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay, half-life measurement, single lab\",\n      \"pmids\": [\"27780719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cyclin A2-Cdk2 binds and phosphorylates CDC20 during interphase, inhibiting APC/C-CDC20 activity. Preventing CDC20 phosphorylation results in premature APC/C-CDC20 activation and destabilization of cyclin B1 and A2, lengthening G2 and slowing mitotic entry. Expressing non-degradable cyclin A2 (but not cyclin B1) restores mitotic entry.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, phospho-mutagenesis, cell synchronization\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay, phospho-mutagenesis, genetic rescue experiment, multiple orthogonal methods\",\n      \"pmids\": [\"26960431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Kinetochore-localized PP1 dephosphorylates CDC20, directing it toward APC/C activation and promoting mitotic exit. Both APC/C activation and inhibition depend on CDC20 fluxing through the same kinetochore binding site; the microtubule attachment status controls the balance between these opposing CDC20 fates.\",\n      \"method\": \"Live imaging, kinase/phosphatase inhibitor experiments, RNAi in C. elegans and human cells\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional genetic and pharmacological dissection of dual CDC20 fate at kinetochores, multiple model systems\",\n      \"pmids\": [\"28698300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CDC20 transcriptionally activates expression of the E2 ubiquitin-conjugating enzyme UbcH10 via its WD40 domain. CDC20 physically interacts with APC/C-CBP/p300 complex, and this complex is recruited to the UBCH10 promoter to drive transcription. This activity is cell cycle-specific.\",\n      \"method\": \"Reporter assay, co-immunoprecipitation, ChIP, WD40 domain mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP of CDC20-CBP/p300 at UBCH10 promoter, domain mutagenesis, co-IP, single lab\",\n      \"pmids\": [\"21454660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"APC/C(CDC20) targets E2F1 for degradation in prometaphase. Ectopic expression of CDC20 reduces E2F1 protein levels; CDC20 knockdown stabilizes E2F1 and leads to its accumulation in prometaphase cells. Co-expression of DP1 with E2F1 blocks APC/C-induced E2F1 degradation.\",\n      \"method\": \"Co-expression experiments, siRNA knockdown, cell synchronization, ubiquitination assay\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CDC20 knockdown stabilizes substrate, rescue by DP1 co-expression, single lab\",\n      \"pmids\": [\"20948288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RAP80 is polyubiquitinated and degraded by APC/C(CDC20) in mitosis (and by APC/C(CDH1) in G1). Knockdown of CDC20 blocks RAP80 degradation during mitosis. A conserved D-box in RAP80 is required for its ubiquitination and stability control by APC/C(CDC20).\",\n      \"method\": \"siRNA knockdown, ubiquitination assay, D-box mutagenesis, cell cycle synchronization\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown phenotype with substrate stabilization, D-box mutagenesis, in vitro ubiquitination, single lab\",\n      \"pmids\": [\"22426463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CDC20 promotes degradation of Axin1 (core member of the β-catenin destruction complex) via its E3 ligase activity, reducing β-catenin phosphorylation and promoting β-catenin nuclear translocation and transcriptional activity in prostate cancer stem-like cells.\",\n      \"method\": \"siRNA knockdown, Western blot for downstream signaling, sphere formation and tumorigenicity assays\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — downstream pathway analysis after CDC20 knockdown, substrate identification by Western blot, single lab without direct ubiquitination assay\",\n      \"pmids\": [\"30904606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"APC/C(CDC20) binds to the D-box motif in PHD3 protein and promotes its polyubiquitination and degradation, thereby stabilizing HIF-1α and promoting VEGF secretion in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, CDC20 knockdown/pharmacological inhibition, PHD3 D-box mutagenesis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay, D-box mutagenesis, but single lab\",\n      \"pmids\": [\"33039559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CDC20 directly targets LC3 (a key autophagy regulator) for ubiquitination and proteasomal degradation, thereby inhibiting autophagy and promoting cardiac hypertrophy.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, rAAV9-mediated cardiac overexpression/knockdown in vivo, in vitro cardiomyocyte assays\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay, in vivo cardiac model, single lab\",\n      \"pmids\": [\"30613277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDC20 specifically interacts with GSDME via its degron and promotes GSDME ubiquitination and proteasomal degradation in a degron-dependent manner, thereby suppressing pyroptosis in prostate cancer cells.\",\n      \"method\": \"Immunoprecipitation, ubiquitination assay, siRNA knockdown, cycloheximide chase assay, in vivo syngeneic mouse models\",\n      \"journal\": \"Experimental hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay, degron-dependency shown, in vivo validation, single lab\",\n      \"pmids\": [\"37528490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDC20 (via its WD40 domain) interacts with the DNA-binding domain of p65 (NF-κB subunit) and promotes APC11-dependent ubiquitination and degradation of p65 to promote osteogenic differentiation. Cdc20 conditional knockout mice display decreased bone formation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, domain mapping, conditional knockout mouse model\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP with domain mapping, ubiquitination assay, in vivo knockout with bone phenotype rescue, multiple orthogonal methods\",\n      \"pmids\": [\"34382737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDC20 assists its own catalytic incorporation into the mitotic checkpoint complex (MCC) as a substrate-assisted catalyst. Simultaneous docking on several sites of the catalytic kinetochore complex is required for CDC20 to access MAD2. The catalyst promotes MCC assembly through spatially and temporally coordinated conformational changes in both MAD2 and CDC20.\",\n      \"method\": \"Reconstituted SAC system, biochemical analysis with purified components, structural/conformational analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted SAC system with purified components, mechanistic dissection of conformational changes, rigorous biochemical characterization\",\n      \"pmids\": [\"33384373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Kinetochore-catalyzed MAD2-CDC20 assembly occurs through a tripartite mechanism: localized delivery of MAD2 and CDC20 substrates plus two phosphorylation-dependent interactions that geometrically constrain their positions and prime CDC20 for MAD2 interaction.\",\n      \"method\": \"Reconstituted kinetochore system, live-cell probe for Mad2-Cdc20 assembly, epistasis with phospho-mutants\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted system, live-cell probe, phospho-mutagenesis, multiple orthogonal approaches\",\n      \"pmids\": [\"33384372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PP1 removes specific inhibitory phosphorylation in the N-terminus of CDC20 to promote APC/C(CDC20)-dependent cyclin B destruction at anaphase onset. Depletion or chemical inhibition of PP1 stabilizes cyclin B and delays metaphase-to-anaphase transition. CDC206A (CDK1 phosphorylation-defective) mutant cells rapidly destroy cyclin B and enter anaphase without PP1 activity.\",\n      \"method\": \"PP1 depletion/inhibition, phospho-mutagenesis (CDC206A), cell biology, cyclin B stability assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — PP1 inhibition/depletion combined with phospho-mutagenesis rescue, clear mechanistic dissection, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"32755477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PP2A-B56 directly binds the disordered Apc1-loop500 domain of APC/C and stimulates CDC20 loading onto APC/C by dephosphorylating CDC20. Mutations in Apc1-loop500 abolishing B56 binding decrease CDC20 loading and APC/C-dependent ubiquitylation. A non-phosphorylatable CDC20 mutant bypasses the need for PP2A-B56.\",\n      \"method\": \"APC/C reconstitution in Xenopus egg extracts, mutagenesis, co-immunoprecipitation, in vitro ubiquitylation assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted APC/C system, mutagenesis, phosphatase specificity determined, multiple orthogonal methods\",\n      \"pmids\": [\"31825153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mps1-phosphorylated Mad1 CTD creates a phosphorylation-specific interaction with CDC20. Together with Mps1-phosphorylation of Bub1, this generates a tripartite assembly of Bub1 and CDC20 onto the C-terminal domain of Mad1, positioning the Mad2-interacting motif (MIM) of CDC20 near open-Mad2 to catalyse formation of C-MAD2:CDC20.\",\n      \"method\": \"Structural analysis (NMR, cross-linking MS), biochemical binding assays, mutagenesis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural data combined with biochemical binding assays and mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"36289199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Human cells express conserved alternative CDC20 translational isoforms initiated at downstream AUGs (e.g., Met43). The truncated Met43 isoform lacks key N-terminal SAC inhibitory binding sites and is resistant to SAC-mediated inhibition, promoting mitotic exit even in the presence of mitotic perturbations. Differential turnover of full-length vs. truncated isoforms during prolonged arrest creates a molecular timer controlling mitotic slippage duration.\",\n      \"method\": \"Isoform-specific mutagenesis, ribosome profiling, cell synchronization, SAC assays, CRISPR engineering\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — engineered CDC20 isoform variants, functional SAC assays, CRISPR-based isoform manipulation, multiple orthogonal methods\",\n      \"pmids\": [\"37100900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BUB-1-bound PLK-1 phosphorylates the ABBA motif of BUB-1 to promote BUB-1-CDC-20 interaction and CDC-20 kinetochore recruitment. This PLK-1 kinase activity at kinetochores is required for CDC-20 localization to kinetochores and timely mitotic progression in C. elegans embryos, functioning in a checkpoint-independent manner.\",\n      \"method\": \"C. elegans genetics, live imaging, phospho-mutagenesis, kinase inhibitor experiments\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic and pharmacological dissection with phospho-mutagenesis, live imaging, C. elegans ortholog study with conserved mechanism\",\n      \"pmids\": [\"37137308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PPM1K (mitochondrial phosphatase regulating BCAA catabolism) maintains MEIS1 and p21 levels by decreasing CDC20-mediated ubiquitination and degradation. PPM1K deficiency leads to increased CDC20-dependent degradation of MEIS1 and p21, reducing HSC glycolysis and quiescence.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, genetic knockout in mice, fluorescent BCAA sensor\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay, in vivo knockout, single lab\",\n      \"pmids\": [\"29719258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CDC20-APC drives invasiveness and self-renewal in glioblastoma stem-like cells (GSCs) through degradation of the pluripotency transcription factor SOX2.\",\n      \"method\": \"shRNA knockdown, overexpression, orthotopic xenograft, Western blot for SOX2 levels\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — knockdown phenotype with substrate identification, in vivo tumor model, single lab\",\n      \"pmids\": [\"26074073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CDC20 maintains glioblastoma tumor initiating cells (TICs) through APC/C-dependent degradation of p21(CIP1/WAF1). CDC20 disruption stabilizes p21, repressing CDC25C, c-Myc, and Survivin. FOXM1 transcriptionally controls CDC20 expression in TICs.\",\n      \"method\": \"RNAi knockdown, ubiquitination assay, ChIP for FOXM1 at CDC20 promoter, chromatin analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay, ChIP, knockdown phenotype, single lab\",\n      \"pmids\": [\"25938542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CDC20 directly interacts with Mcl-1 (anti-apoptotic Bcl-2 family member), and this interaction is required for Mcl-1 stability. Knockdown of CDC20 suppresses Mcl-1 expression, inhibits p-Chk1, impairs Rad51-mediated DNA repair, and induces apoptosis in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown assay, siRNA knockdown, in vivo radiosensitization study\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and GST pulldown confirming direct interaction, functional consequence of knockdown, single lab\",\n      \"pmids\": [\"32932732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cdc20 and PC-PLC co-immunoprecipitate and co-localize in the perinuclear endoplasmic reticulum (JUNQ compartment) in rat hepatoma cells. Cdc20 overexpression alters PC-PLC subcellular localization and causes its degradation via the ubiquitin-proteasome pathway, demonstrating APC/C(Cdc20) targets PC-PLC.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy co-localization, overexpression, proteasome inhibitor experiment\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP and co-localization, single lab, single method for ubiquitin-mediated degradation, non-canonical substrate\",\n      \"pmids\": [\"19347873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A second Mad2-binding domain on CDC20 was identified in amino acids 342-355 within the WD repeat region. An intervening region between this domain and the previously known N-terminal domain (aa 111-150) interferes with Mad2 binding when either domain is present alone. Optimal Mad2 binding requires coordination of three domains. A polyhistidine motif adjacent to the second binding domain may maintain CDC20 conformation for Mad2 binding.\",\n      \"method\": \"Co-immunoprecipitation and co-localization with CDC20 deletion mutants, peptide inhibition assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — systematic deletion mutant analysis with co-IP and co-localization, multiple mutants tested, single lab\",\n      \"pmids\": [\"16497171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cdc20 downregulation or APC/C inhibition induces premature senescence in normal lung fibroblasts through GSK-3β-mediated phosphorylation and downregulation of securin. In NSCLC cells (which bypass senescence), the same pathway induces apoptosis through securin downregulation.\",\n      \"method\": \"siRNA knockdown, APC/C pharmacological inhibitor, GSK-3β inhibitor rescue, Western blot for securin phosphorylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway dissection via multiple inhibitors and knockdown, cell-type-specific phenotype, single lab\",\n      \"pmids\": [\"35988650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In Drosophila, BubR1 (but not Mad2) is required for CDC20 recruitment to kinetochores. BubR1 and Mad2 can bind CDC20 independently, and their interactions are enhanced during mitotic arrest. This demonstrates that BubR1 provides the primary kinetochore-CDC20 recruitment mechanism in flies.\",\n      \"method\": \"RNAi in Drosophila S2 cells and syncytial embryos, live imaging, co-immunoprecipitation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi dissection with co-IP, live imaging, Drosophila ortholog study with clear mechanistic distinction from vertebrates\",\n      \"pmids\": [\"20421417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRMT6 maintains CDC20 transcription via H3R2me2a histone methylation at the CDC20 promoter. CDC20 in turn interacts with CDKN1B (p27) and destabilizes it via ubiquitin-mediated degradation, promoting GBM cell proliferation.\",\n      \"method\": \"ChIP-qPCR for PRMT6/H3R2me2a at CDC20 promoter, co-immunoprecipitation for CDC20-CDKN1B, ubiquitination assay, rescue experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP evidence for PRMT6 regulation of CDC20 transcription, co-IP and ubiquitination for CDC20-CDKN1B, single lab\",\n      \"pmids\": [\"36792756\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDC20 is an essential WD40-repeat co-activator of the APC/C E3 ubiquitin ligase that directly recognizes substrates (cyclin B, securin, cyclin A, Bim, E2F1, RAP80, PHD3, LC3, p65, GSDME, and others) via its N-terminus and WD40 domain, activates APC/C to drive anaphase onset and mitotic exit, and is itself regulated by a cycle of CDK1-mediated phosphorylation (which inhibits APC/C binding) countered by PP1/PP2A-B56-mediated dephosphorylation (which promotes APC/C binding), by MAD2/BubR1-containing MCC formation at unattached kinetochores that sequesters CDC20 away from APC/C, by Bub1-Plk1-mediated phosphorylation providing an MCC-independent APC/C inhibitory mechanism, and by APC15-facilitated autoubiquitylation that drives MCC disassembly; beyond mitosis, CDC20-APC also controls dendrite morphogenesis, presynaptic differentiation, osteogenesis (via p65 degradation), and autophagy (via LC3 degradation) in postmitotic cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDC20 is the essential mitotic co-activator of the anaphase-promoting complex/cyclosome (APC/C), a WD40-repeat protein that confers substrate specificity on this E3 ubiquitin ligase to drive the metaphase-to-anaphase transition and mitotic exit [#1, #5]. It exists in distinct cell-cycle forms — inactive MAD2-CDC20-APC at metaphase and active CDC20-APC at anaphase — and recognizes substrates directly through its N-terminus independently of the APC/C core, with the N-terminus serving as the specificity determinant [#0, #5]. CDC20 abundance and activity are tightly periodic, peaking at M phase and falling at the M/G1 transition through proteasomal degradation and APC/C-dependent autoubiquitylation in cis [#3, #16]. Its activity is gated by a phosphorylation switch: CDK1/cyclin A-Cdk2 phosphorylation of conserved N-terminal threonines inhibits APC/C binding, while mitotic PP2A-B56 (acting at the Apc1-loop500) and kinetochore PP1 dephosphorylate CDC20 to license APC/C loading and substrate destruction including cyclin B [#19, #24, #36, #37]. The spindle assembly checkpoint restrains CDC20 by two routes — MAD2 binds a site required for APC/C association and competes with the APC/C for CDC20, and Bub1-scaffolded Plk1 phosphorylation provides an MCC-independent inhibitory mechanism [#18, #22]; kinetochores catalyze MAD2-CDC20 (MCC) assembly through phosphorylation-dependent, geometrically constrained delivery of MAD2 and CDC20, with CDC20 itself acting as a substrate-assisted catalyst of its own incorporation [#34, #35, #38]. APC/C-CDC20 substrates extend across mitotic regulators (cyclin A, securin, E2F1, RAP80) and, in postmitotic and disease contexts, to Bim, p65, GSDME, LC3, p21, and SOX2, linking CDC20 to apoptosis, autophagy, osteogenic differentiation, neuronal dendrite morphogenesis, and tumor cell self-renewal [#8, #9, #10, #15, #20, #27, #28, #33]. CDC20 levels are themselves set transcriptionally, being repressed by p53 under genotoxic stress and activated by FOXM1 and PRMT6, and post-translationally controlled by SPOP-Cullin3 and Parkin [#13, #21, #23, #43, #49].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established that the mammalian CDC20 ortholog p55CDC is a cell-cycle protein that associates, via its WD repeats, with a kinase activity peaking at M phase — the first hint that it operates within a mitotic regulatory complex.\",\n      \"evidence\": \"Immunoprecipitation, kinase assay, and immunolocalization in cycling mammalian cells\",\n      \"pmids\": [\"7513050\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Associated kinase not identified\", \"No demonstration of APC/C function or substrate\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed CDC20 protein is cell-cycle periodic and that its destruction at M/G1 requires the 26S proteasome, tying CDC20 turnover to mitotic exit.\",\n      \"evidence\": \"Cell synchronization with proteasome inhibition and immunolocalization\",\n      \"pmids\": [\"9353311\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin ligase responsible not defined\", \"Mechanism of degradation (autoubiquitylation vs other) not resolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined CDC20 as the APC/C activator whose checkpoint inhibition is mediated by MAD2, and established it as the physical bridge linking MAD2 to APC/C subunits — placing CDC20 at the heart of the spindle checkpoint.\",\n      \"evidence\": \"In vitro reconstitution with recombinant proteins, Xenopus microinjection, reciprocal co-IP of MAD2/CDC20/APC components, live imaging\",\n      \"pmids\": [\"9637688\", \"9628895\", \"9736712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of MAD2-CDC20 binding undefined\", \"How CDC20 selects substrates not yet shown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Resolved how CDC20 confers substrate specificity, showing its N-terminus binds APC/C substrates directly and independently of the APC/C core.\",\n      \"evidence\": \"In vitro binding, chimeric proteins, and ubiquitination assays without APC/C\",\n      \"pmids\": [\"11562349\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full repertoire of recognition motifs (D-box vs KEN) not enumerated here\", \"Role of WD40 domain in substrate binding addressed only later\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that CDK/MAPK phosphorylation of CDC20 does not block APC/C activation per se but controls its affinity for checkpoint proteins, defining CDC20 phosphorylation as the substrate of checkpoint control.\",\n      \"evidence\": \"In vitro kinase and APC/C assays with phospho-site mutagenesis in Xenopus extracts\",\n      \"pmids\": [\"12855955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Counteracting phosphatase not identified at this stage\", \"Precise residues governing each checkpoint-protein interaction not fully mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Explained how cyclin A is degraded despite an active checkpoint, showing CDC20 binds cyclin A with little associated Mad2 to permit checkpoint-independent destruction.\",\n      \"evidence\": \"Reciprocal co-IP, in vitro ubiquitination, and RNAi with synchronization\",\n      \"pmids\": [\"18471975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for Cks-dependent recognition unresolved\", \"Why cyclin A escapes checkpoint while cyclin B does not only partially explained\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended CDC20-APC function beyond mitosis into postmitotic neurons, showing centrosomal CDC20-APC controls dendrite morphogenesis and degrades NeuroD2 to drive presynaptic differentiation.\",\n      \"evidence\": \"In vivo knockdown in rat cerebellum, live imaging, ubiquitination assays, and genetic epistasis\",\n      \"pmids\": [\"19167333\", \"19900895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CDC20-APC is activated in postmitotic cells lacking cell-cycle cues unclear\", \"Full neuronal substrate set undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Dissected the two-pronged regulation of CDC20: CDK phosphorylation of N-terminal threonines blocks APC/C binding while mitotic PP2A removes them, and MAD2 directly competes with APC/C for CDC20 — defining the phosphorylation switch and a non-pseudosubstrate checkpoint mechanism.\",\n      \"evidence\": \"In vitro kinase/phosphatase assays, Xenopus extracts, competition binding, and in vivo checkpoint mutagenesis\",\n      \"pmids\": [\"22713866\", \"23007648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the in vivo kinetochore phosphatase not yet pinned\", \"Coordination between MAD2 competition and phospho-control not integrated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified APC15 as the subunit enabling APC/C(MCC)-dependent CDC20 autoubiquitylation that drives MCC disassembly, providing the mechanism for checkpoint silencing.\",\n      \"evidence\": \"RNAi depletion and in vitro ubiquitylation with reconstituted human APC/C\",\n      \"pmids\": [\"22079111\", \"23007861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How substrate levels tune the autoubiquitylation/disassembly balance not fully quantified\", \"Structural arrangement at the MCC-binding site addressed only later\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed an MCC-independent checkpoint mechanism in which Bub1 directly and Plk1-scaffolded phosphorylation of CDC20 inhibits APC/C(CDC20), and showed interphase cyclin A2-Cdk2 phosphorylation of CDC20 sets the timing of mitotic entry.\",\n      \"evidence\": \"In vitro kinase and APC/C inhibition assays, phospho-mutagenesis with RNAi in human cells, and genetic rescue with non-degradable cyclin A2\",\n      \"pmids\": [\"26912231\", \"26960431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of MCC vs Bub1-Plk1 phosphorylation in vivo not quantified\", \"Crosstalk between interphase and mitotic phospho-control unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed that APC/C activation and inhibition both depend on CDC20 fluxing through a single kinetochore site, with PP1 dephosphorylation directing CDC20 toward APC/C activation and microtubule attachment status setting the balance.\",\n      \"evidence\": \"Live imaging with kinase/phosphatase inhibitors and RNAi in C. elegans and human cells\",\n      \"pmids\": [\"28698300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular determinant that switches CDC20 fate at the shared site not fully defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapped the phosphatases that license CDC20-APC/C loading, showing PP2A-B56 binds the Apc1-loop500 to dephosphorylate CDC20 and PP1 removes N-terminal inhibitory phosphorylation to permit cyclin B destruction at anaphase.\",\n      \"evidence\": \"Reconstituted APC/C in Xenopus extracts, PP1 depletion/inhibition, and CDC20 phospho-mutant rescue\",\n      \"pmids\": [\"31825153\", \"32755477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial coordination of PP1 vs PP2A-B56 action on CDC20 not integrated\", \"How phosphatase activity is locally controlled at kinetochores unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the mechanism of kinetochore-catalyzed MCC assembly, showing CDC20 is a substrate-assisted catalyst whose own multi-site docking and phosphorylation-dependent geometric constraints prime MAD2 capture.\",\n      \"evidence\": \"Reconstituted SAC/kinetochore systems with purified components, conformational analysis, live-cell probes, and phospho-mutagenesis\",\n      \"pmids\": [\"33384373\", \"33384372\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full structural intermediate of the assembly reaction not solved\", \"Kinetics of catalysis in living cells only inferred\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Broadened CDC20 substrate biology into differentiation and cell death, establishing WD40-mediated degradation of NF-kB p65 in osteogenesis with an in vivo bone phenotype.\",\n      \"evidence\": \"Co-IP with domain mapping, APC11-dependent ubiquitination assays, and conditional knockout mice\",\n      \"pmids\": [\"34382737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CDC20-APC is engaged in non-dividing osteoblasts not detailed\", \"Relationship to mitotic CDC20 regulation unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered an additional layer of CDC20 control: alternative translational isoforms (e.g. Met43) lacking N-terminal SAC sites resist checkpoint inhibition and act as a molecular timer for mitotic slippage, and a conserved Bub1-Plk1/ABBA pathway recruits CDC20 to kinetochores independent of the checkpoint.\",\n      \"evidence\": \"Ribosome profiling, isoform-specific and CRISPR engineering with SAC assays; C. elegans genetics and live imaging with phospho-mutagenesis\",\n      \"pmids\": [\"37100900\", \"37137308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological triggers selecting isoform usage not defined\", \"How checkpoint-independent kinetochore recruitment integrates with MCC formation unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CDC20's many non-mitotic substrates and its transcriptional/post-translational regulators are coordinated across distinct cell types, and the structural basis for switching between substrate ubiquitylation and self-inhibition, remain to be integrated.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking mitotic vs postmitotic CDC20 activation\", \"Many cancer-context substrates rest on single-lab Co-IP/knockdown without reconstitution\", \"Direct E3 ligase mechanism for several non-canonical substrates not biochemically resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 8, 20, 28, 30, 33]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 5, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 5, 8, 16, 24, 36]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 8, 16, 17, 20, 33]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [20, 32, 47]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [31]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 10, 33]}\n    ],\n    \"complexes\": [\"APC/C\", \"Mitotic checkpoint complex (MCC)\"],\n    \"partners\": [\"MAD2\", \"BUBR1\", \"CDC27\", \"BUB1\", \"AURKA\", \"PP2A-B56\", \"PP1\", \"MAD1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}