Coupling of Cdc20 inhibition and activation by BubR1

J Cell Biol. 2021 May 3;220(5):e202012081. doi: 10.1083/jcb.202012081.

Abstract

Tight regulation of the APC/C-Cdc20 ubiquitin ligase that targets cyclin B1 for degradation is important for mitotic fidelity. The spindle assembly checkpoint (SAC) inhibits Cdc20 through the mitotic checkpoint complex (MCC). In addition, phosphorylation of Cdc20 by cyclin B1-Cdk1 independently inhibits APC/C-Cdc20 activation. This creates a conundrum for how Cdc20 is activated before cyclin B1 degradation. Here, we show that the MCC component BubR1 harbors both Cdc20 inhibition and activation activities, allowing for cross-talk between the two Cdc20 inhibition pathways. Specifically, BubR1 acts as a substrate specifier for PP2A-B56 to enable efficient Cdc20 dephosphorylation in the MCC. A mutant Cdc20 mimicking the dephosphorylated state escapes a mitotic checkpoint arrest, arguing that restricting Cdc20 dephosphorylation to the MCC is important. Collectively, our work reveals how Cdc20 can be dephosphorylated in the presence of cyclin B1-Cdk1 activity without causing premature anaphase onset.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphase / physiology
  • Anaphase-Promoting Complex-Cyclosome / metabolism
  • Cdc20 Proteins / metabolism*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cyclin B1 / metabolism
  • HeLa Cells
  • Humans
  • M Phase Cell Cycle Checkpoints / physiology
  • Mitosis / physiology
  • Phosphorylation / physiology
  • Protein Binding / physiology
  • Protein Serine-Threonine Kinases / metabolism*
  • Spindle Apparatus / metabolism

Substances

  • Cdc20 Proteins
  • Cell Cycle Proteins
  • Cyclin B1
  • CDC20 protein, human
  • Anaphase-Promoting Complex-Cyclosome
  • BUB1 protein, human
  • Protein Serine-Threonine Kinases