TRIP13 Functions in the Establishment of the Spindle Assembly Checkpoint by Replenishing O-MAD2

Cell Rep. 2018 Feb 6;22(6):1439-1450. doi: 10.1016/j.celrep.2018.01.027.

Abstract

The spindle assembly checkpoint (SAC) prevents premature segregation of chromosomes during mitosis. This process requires structural remodeling of MAD2 from O-MAD2 to C-MAD2 conformation. After the checkpoint is satisfied, C-MAD2 is reverted to O-MAD2 to allow anaphase-promoting complex/cyclosome (APC/C) to trigger anaphase. Recently, the AAA+-ATPase TRIP13 was shown to act in concert with p31comet to catalyze C- to O-MAD2. Paradoxically, although C-MAD2 is present in TRIP13-deficient cells, the SAC cannot be activated. Using a degron-mediated system to uncouple TRIP13 from O- and C-MAD2 equilibrium, we demonstrated that the loss of TRIP13 did not immediately abolish the SAC, but the resulting C-MAD2-only environment was insufficient to enable the SAC. These results favor a model in which MAD2-CDC20 interaction is coupled directly to the conversion of O- to C-MAD2 instead of one that involves unliganded C-MAD2. TRIP13 replenishes the O-MAD2 pool for activation by unattached kinetochores.

Keywords: MAD2; TRIP13; mitosis; spindle assembly checkpoint.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / metabolism*
  • Cdc20 Proteins / metabolism
  • Cell Cycle Proteins / metabolism*
  • Chromosome Segregation / physiology*
  • HeLa Cells
  • Humans
  • Kinetochores / metabolism
  • M Phase Cell Cycle Checkpoints / physiology*
  • Mad2 Proteins / metabolism*

Substances

  • Cdc20 Proteins
  • Cell Cycle Proteins
  • MAD2L1 protein, human
  • Mad2 Proteins
  • CDC20 protein, human
  • ATPases Associated with Diverse Cellular Activities
  • TRIP13 protein, human