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Paradoxical mitotic exit induced by a small molecule inhibitor of APC/CCdc20

Katherine V Richeson1, Tatyana Bodrug2, Katharine L Sackton1

  • 1Department of Cell Biology, Harvard Medical School, Boston, MA, USA.

Nature Chemical Biology
|March 11, 2020
PubMed

Insights

The anaphase-promoting complex/cyclosome (APC/C) inhibitor apcin shortens mitosis when the spindle assembly checkpoint (SAC) is active. Apcin prolongs mitosis when SAC is inactive, revealing context-dependent effects of small molecules.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The anaphase-promoting complex/cyclosome (APC/C) is a crucial ubiquitin ligase regulating cell cycle progression.
  • APC/C activity is tightly controlled by activators like Cdc20 and inhibitors such as the mitotic checkpoint complex (MCC).
  • The spindle assembly checkpoint (SAC) activates MCC to delay mitotic exit when chromosomes are not properly aligned.

Purpose of the Study:

  • To investigate the paradoxical effects of the APC/C inhibitor apcin on mitosis.
  • To elucidate the mechanism by which apcin alters mitosis duration under different spindle assembly checkpoint (SAC) activities.
  • To explore the interaction of apcin with other regulatory proteins like p31comet.

Main Methods:

  • Small molecule inhibitor screening.
  • Cell cycle analysis using microscopy and flow cytometry.
  • Biochemical assays to study protein-protein interactions and ubiquitination.

Main Results:

  • Apcin, a Cdc20 ligand, inhibits APC/CCdc20 and prolongs mitosis when SAC is low.
  • Paradoxically, apcin shortens mitosis when SAC activity is high.
  • Apcin targets a common binding site on Cdc20, affecting both substrate ubiquitination and MCC-dependent inhibition.
  • Apcin cooperates with p31comet to relieve MCC-mediated APC/C inhibition.

Conclusions:

  • Apcin exhibits context-dependent regulation of APC/C activity.
  • Apcin can either inhibit or activate APC/C, leading to prolonged or shortened mitosis, respectively, based on SAC status.
  • This study demonstrates how a single small molecule can elicit opposing biological outcomes by modulating protein interactions within a regulatory network.

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