Mitotic slippage is determined by p31comet and the weakening of the spindle-assembly checkpoint

Tsun Ming Lok,Yang Wang,Wendy Kaichun Xu,Randy Y C Poon,Siwei Xie,Hoi Tang Ma

doi:10.1038/s41388-020-1187-6

Abstract

Mitotic slippage involves cells exiting mitosis without proper chromosome segregation. Although degradation of cyclin B1 during prolonged mitotic arrest is believed to trigger mitotic slippage, its upstream regulation remains obscure. Whether mitotic slippage is caused by APC/CCDC20 activity that is able to escape spindle-assembly checkpoint (SAC)-mediated inhibition, or is actively promoted by a change in SAC activity remains an outstanding issue. We found that a major culprit for mitotic slippage involves reduction of MAD2 at the kinetochores, resulting in a progressive weakening of SAC during mitotic arrest. A further level of control of the timing of mitotic slippage is through p31comet-mediated suppression of MAD2 activation. The loss of kinetochore MAD2 was dependent on APC/CCDC20, indicating a feedback control of APC/C to SAC during prolonged mitotic arrest. The gradual weakening of SAC during mitotic arrest enables APC/CCDC20 to degrade cyclin B1, cumulating in the cell exiting mitosis by mitotic slippage.

Highlights

The entire cell physiological environment is reorganized during mitosis to facilitate division
We found that reduction of MAD2 at the kinetochores during mitotic arrest initiates a weakening of the spindle-assembly checkpoint (SAC), thereby enabling APC/CCDC20 to degrade cyclin B1 in a proteasome-dependent manner to promote mitotic slippage
The gradual loss of cyclin B1 is consistent with its role in mitotic slippage, which was confirmed by the loss of mitotic markers including phosphorylated histone H3Ser10 and CDC27 (Fig. 1d)

Summary

Introduction

The entire cell physiological environment is reorganized during mitosis to facilitate division. All the cellular changes are reversed to return the daughter cells to interphase. Cyclin-dependent kinase 1 (CDK1) and its activating subunit cyclin B1 are essential components of the mitotic engine. The destruction of cyclin B1, enforced by a ubiquitin ligase comprised of anaphase-promoting complex/cyclosome and its targeting subunit CDC20 (APC/CCDC20), is a key event. These authors contributed : Tsun Ming Lok, Yang Wang, Wendy Kaichun Xu

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Conclusion