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#Cdc20

3 public questions tagged with this topic.

Cell Cycle Regulation

What happens if APC/C-Cdc20 is inhibited?

Anaphase-promoting complex bound to coactivator Cdc20 represents irreversible executor of metaphase exit, targeting securin and cyclin B. Inhibition of this ligase through multiple mechanisms arrests cells before chromosome separation. Endogenous inhibition occurs during spindle checkpoint activation where Mitotic Checkpoint Complex binds APC/C core blocking substrate recruitment. Exogenous inhibitors apcin occupying D-box binding pocket on Cdc20 and proTAME blocking APC/C activation, or depletion of Cdc20 protein itself, mimic checkpoint. Consequence is persistence of securin which continues to bind and suppress separase protease, and persistence of cyclin B maintaining high CDK1-phosphorylation of lamins, condensins and microtubule regulators. Cohesin rings at centromeres therefore remain intact, as separase cannot access Scc1 cleavage site, leaving sister chromatids interlinked despite bipolar spindle tension attempting to pull. Phenotypically cells display metaphase plate with fully aligned chromosomes but inability to initiate anaphase A movement. Prolonged arrest leads to mitotic slippage through slow cyclin B leakage, cohesion fatigue with partial separation, cell death or formation of tetraploid G1 cells after aberrant exit, illustrating essential role of APC/C-Cdc20 for timely anaphase.

Ref: Pines, Mitotic Exit Regulation by APC/C-Cdc20, Nat Rev Mol Cell Biol 2011; NCBI Bookshelf, Consequences of APC/C Inhibition.

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Cell Cycle Regulation

Which protein deactivates mitotic CDKs during mitotic exit?

Mitotic exit requires not only destruction of cyclin B but comprehensive reversal of CDK1-Cyclin B phosphorylation on hundreds of substrates. Specialized phosphatases execute this program. In budding yeast, Cdc14 is the master phosphatase. Most of the cell cycle it is sequestered in nucleolus bound to inhibitor Net1 or Cfi1. Two release pathways operate sequentially: the Cdc Fourteen Early Anaphase Release pathway involving separase, Slk19, Spo12 and Zds1/Zds2 provides transient liberation in early anaphase, while the Mitotic Exit Network composed of Tem1, Cdc15 and Dbf2-Mob1 kinases sustains release. Active Cdc14 preferentially dephosphorylates serine followed by proline with basic Lys in +3 position, matching CDK consensus, including targets Cdh1 converting APC/C coactivator from Cdc20 to Cdh1, Swi5 transcription factor enabling Sic1 inhibitor synthesis and Cdc15 reinforcing feedback. In mammals, CDC14A/B and PP2A-B55, regulated by Greatwall-ENSA pathway, fulfill analogous roles. Inhibition traps cells in late anaphase with segregated but condensed chromosomes unable to reform nuclei or undergo cytokinesis. Additional feedback loops involving polo-like kinases, phosphatases and SCF-mediated degradation reinforce irreversibility and protect against premature progression that would compromise genome integrity and viability.

Ref: Stegmeier & Amon, Closing Mitosis: Role of Cdc14 Phosphatases, Annu Rev Genet 2004; Alberts et al., Chapter 17, Mitotic Exit Control.

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Cell Cycle Regulation

What happens if Cdc20 is inhibited?

Anaphase entry requires anaphase-promoting complex/cyclosome (APC/C) activated by co-activator Cdc20, which targets securin and cyclin B for proteasomal degradation via K11-linked polyubiquitination. Securin normally binds and inhibits separase, protease that cleaves cohesin subunit Rad21 holding sister chromatids together. When APC/C-Cdc20 destroys securin, liberated separase removes cohesin, allowing sister chromatids to separate toward opposite poles. If Cdc20 is absent, inhibited by MCC, or chemically blocked, APC/C remains inactive, securin and cyclin B persist, separase stays inhibited, cohesin remains intact, and sister chromatids continue to cohere at metaphase plate despite spindle forces. Chromosomes therefore fail to separate, producing metaphase arrest with high CDK1 activity preventing mitotic exit. Conversely, premature Cdc20 activation causes early separase release and aneuploidy. Depletion experiments in yeast and mammalian cells show non-disjunction and prolonged checkpoint activation upon Cdc20 knockdown, while overexpression drives tumorigenesis through chromosomal instability. Hence Cdc20 inhibition specifically blocks chromosome segregation step, not DNA replication. Ubiquitin ligase APC/C conjugates K11-linked chains via Ube2S elongating enzyme after initial ubiquitination by UbcH10, creating signals recognized by 26S proteasome for rapid degradation, and this sequential ubiquitination ensures irreversible commitment to anaphase only after checkpoint silencing, preventing reversal that would cause partial segregation and chromothripsis.

Ref: Peters, Nature Rev Mol Cell Biol 2006, APC/C and Cdc20; Sivakumar & Gorbsky, Nature Rev Mol Cell Biol 2015, Spindle Checkpoint.

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