#anaphase-promoting complex

Cell Division

Which factor regulates the exit of cells from mitosis?

Exit from mitosis, defined transition from high CDK1 activity driving chromosome condensation and spindle assembly to low CDK state permitting G1 growth, is regulated primarily by anaphase-promoting complex/cyclosome APC/C ubiquitin ligase. After anaphase onset mediated by APC/C-Cdc20 degradation of securin and cyclin B, second wave of APC/C activity associated with coactivator Cdh1 becomes dominant as CDK1 inactivation allows Cdc14 and PP2A phosphatases to dephosphorylate Cdh1 permitting its binding. APC/C-Cdh1 polyubiquitinates remaining mitotic cyclin B, Polo-like kinase, Aurora kinases A a

Ref: Sullivan & Morgan, Nature Rev Mol Cell Biol 2007, Mitotic Exit Control. Alberts 7th ed., Chapter 17.

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Cell Cycle Regulation

Which factor regulates the exit from mitosis?

Finishing mitosis demands comprehensive reversal of CDK1 mediated phosphorylations and elimination of cyclin B activity. Cdc14 family phosphatases coordinate this program. In budding yeast, Cdc14 resides sequestered in nucleolus bound to inhibitor Net1 also called Cfi1. Mitotic entry maintains sequestration via high CDK activity. In early anaphase, FEAR pathway comprising separase, Slk19 homodimer, Spo12, Zds1 and Zds2 induces transient release. Subsequently Mitotic Exit Network MEN, Hippo-like cascade of Tem1 GTPase localized at daughter spindle pole body, polo kinase Cdc15 and Dbf2-Mob1 comp

Ref: Stegmeier & Amon, Closing Mitosis: Regulation of Cdc14 Phosphatase, Annu Rev Genet 2004; Bardin & Amon, MEN and Mitotic Exit.

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Cell Cycle Regulation

The metaphase-to-anaphase transition is triggered by:

The metaphase to anaphase transition is irreversible decision point governed by ubiquitin dependent proteolysis. When every chromosome achieves amphitelic kinetochore-microtubule attachment generating inter-kinetochore tension, spindle assembly checkpoint signaling through MCC production ceases. Dynein-mediated stripping of Mad1-Mad2 from kinetochores and p31comet-TRIP13 catalyzed MCC disassembly liberate coactivator Cdc20, enabling APC/C-Cdc20 ligase activation. Active APC/C polyubiquitinates securin via destruction box motif and cyclin B via D-box for rapid degradation by 26S proteasome. Sec

Ref: Peters, Anaphase Promoting Complex Orchestrating Metaphase-Anaphase Transition, Nat Rev Mol Cell Biol 2006; Alberts et al., Chapter 18, Anaphase.

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Cell Cycle Regulation

APC/C-Cdh1 is required for:

After separase cleavage of cohesin and chromosome segregation, cells must eliminate remaining mitotic cyclins to establish low CDK environment permissive for origin licensing, transcription reactivation and cytokinesis in G1. Two sequential APC/C coactivators accomplish temporal ordering. APC/C-Cdc20 initiates anaphase by destroying securin and majority of cyclin B during metaphase to anaphase transition. Cdc20 itself then becomes substrate for APC/C-Cdh1. Cdh1, also known as Fzr1, associates with APC/C core from late anaphase through G1, recognizing extended degron repertoire including KEN-bo

Ref: Lindon, APC/C-Cdh1 Control of G1 Homeostasis, Biochem J 2008; Peters, Anaphase Promoting Complex Mechanism and Regulation.

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