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How cyclin A destruction escapes the spindle assembly checkpoint

Barbara Di Fiore1, Jonathon Pines

  • 1Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, England, UK.

The Journal of Cell Biology
|August 25, 2010
PubMed

Insights

The anaphase-promoting complex/cyclosome (APC/C) coactivator Cdc20 and cyclin A

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The anaphase-promoting complex/cyclosome (APC/C) is a crucial ubiquitin ligase regulating mitosis by controlling protein degradation.
  • The spindle assembly checkpoint (SAC) normally inhibits APC/C activity via its coactivator Cdc20 until metaphase.
  • Early mitotic substrates like cyclin A are degraded even when the SAC is active, a process not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which cyclin A degradation occurs independently of the spindle assembly checkpoint.
  • To investigate the roles of Cdc20 and cyclin-dependent kinase cofactor Cks in checkpoint-resistant cyclin A destruction.

Main Methods:

  • Investigated protein-protein interactions using binding assays.
  • Assessed the necessity and sufficiency of Cks in cyclin A degradation.
  • Examined the competition between cyclin A and SAC proteins for Cdc20 binding.

Main Results:

  • Demonstrated direct binding of cyclin A's N terminus to Cdc20, outcompeting SAC proteins.
  • Showed that Cks is essential and sufficient for promoting cyclin A degradation in the presence of an active SAC.
  • Identified Cks as the mediator that recruits the cyclin A-Cdc20 complex to the APC/C.

Conclusions:

  • Cyclin A binding to Cdc20 overrides the SAC, enabling degradation.
  • Cks facilitates checkpoint-resistant degradation by linking the cyclin A-Cdc20 complex to the APC/C.
  • This mechanism ensures timely degradation of key mitotic regulators, maintaining cell cycle fidelity.

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