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Spatiotemporal regulation of the anaphase-promoting complex in mitosis

Key Points

  • The APC/C (anaphase-promoting complex; also known as the cyclosome) is an E3 ubiquitin ligase that mediates the ubiquitylation of key substrates for their degradation by the proteasome at precise times during mitotic progression.

  • Although APC/C activity is most apparent in targeting securin and cyclin B1 to promote anaphase and mitotic exit, the APC/C functions throughout mitosis.

  • Spatiotemporal regulation of APC/C activity promotes substrate degradation at defined times within distinct cellular compartments.

  • The APC/C has several positive and negative regulators, including kinases and protein phosphatases, binding with co-activators CDC20 or CDC20 homologue 1 (CDH1), and with inhibitors such as the mitotic checkpoint complex (MCC).

  • Co-activator proteins recruit substrates to the APC/C and cause conformational changes in the APC/C, fostering increased activity of the E2 ubiquitin-conjugating enzymes that initiate and elongate ubiquitin chains on substrates.

  • The MCC is the effector of the spindle checkpoint signalling pathway. Binding of the MCC to the APC/C inhibits substrate recruitment and ubiquitin chain formation.

  • Dynamic turnover of the MCC, which is partly due to the synthesis and degradation of CDC20, is essential for timely targeting of securin and cyclin B1 after silencing of the spindle checkpoint when chromosomes align at metaphase.

Abstract

The appropriate timing of events that lead to chromosome segregation during mitosis and cytokinesis is essential to prevent aneuploidy, and defects in these processes can contribute to tumorigenesis. Key mitotic regulators are controlled through ubiquitylation and proteasome-mediated degradation. The APC/C (anaphase-promoting complex; also known as the cyclosome) is an E3 ubiquitin ligase that has a crucial function in the regulation of the mitotic cell cycle, particularly at the onset of anaphase and during mitotic exit. Co-activator proteins, inhibitor proteins, protein kinases and phosphatases interact with the APC/C to temporally and spatially control its activity and thus ensure accurate timing of mitotic events.

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Figure 1: Ordered degradation of APC/C substrates.
Figure 2: Structural organization of the APC/C.
Figure 3: Conformational changes during APC/C activation and inactivation.
Figure 4: MCC turnover during mitosis.
Figure 5: Positive and negative modulators control rapid changes in APC/C activity.
Figure 6: Hypothesis for the spatiotemporal regulation of the APC/C in mitosis.

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Acknowledgements

The authors thank the reviewers for critically reading the manuscript and providing suggestions. They also thank A. R. Tipton and L. A. Diaz-Martinez for discussions and suggestions on the manuscript. They apologize to authors whose work they could not cite owing to space constraints.

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Glossary

Monoubiquitylation

The addition of a single ubiquitin to a target protein.

Securin

A protein inhibitor of the protease separase.

Nuclear mitotic apparatus protein

(NUMA). A protein that partners with dynein in the assembly and maintenance of spindle poles.

Dynein–dynactin complex

A microtubule motor complex involved in the transport of spindle checkpoint proteins from kinetochores to the spindle pole.

Cohesin complex

A protein complex that holds replicated sister chromatids together before anaphase.

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Sivakumar, S., Gorbsky, G. Spatiotemporal regulation of the anaphase-promoting complex in mitosis. Nat Rev Mol Cell Biol 16, 82–94 (2015). https://doi.org/10.1038/nrm3934

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