Abstract
According to the prevailing 'clock' model, chromosome decondensation and nuclear envelope reformation when cells exit mitosis are byproducts of Cdk1 inactivation at the metaphase-anaphase transition, controlled by the spindle assembly checkpoint. However, mitotic exit was recently shown to be a function of chromosome separation during anaphase, assisted by a midzone Aurora B phosphorylation gradient - the 'ruler' model. Here we found that Cdk1 remains active during anaphase due to ongoing APC/CCdc20- and APC/CCdh1-mediated degradation of B-type Cyclins in Drosophila and human cells. Failure to degrade B-type Cyclins during anaphase prevented mitotic exit in a Cdk1-dependent manner. Cyclin B1-Cdk1 localized at the spindle midzone in an Aurora B-dependent manner, with incompletely separated chromosomes showing the highest Cdk1 activity. Slowing down anaphase chromosome motion delayed Cyclin B1 degradation and mitotic exit in an Aurora B-dependent manner. Thus, a crosstalk between molecular 'rulers' and 'clocks' licenses mitotic exit only after proper chromosome separation.
Highlights
The decision to enter and exit mitosis is critical for genome stability and the control of tissue homeostasis, perturbation of which has been linked to cancer (Evan and Vousden, 2001; Hanahan and Weinberg, 2011)
Cyclin B1 continues to be degraded during anaphase and its disappearance is a strong predictor of mitotic exit in metazoans
Our work reveals that degradation of B-type Cyclins during anaphase is rate-limiting for mitotic exit among animals that diverged more than 900 million years ago
Summary
The decision to enter and exit mitosis is critical for genome stability and the control of tissue homeostasis, perturbation of which has been linked to cancer (Evan and Vousden, 2001; Hanahan and Weinberg, 2011). The prevailing ‘clock’ model conceives that mitotic exit results from APC/CCdc20-mediated Cyclin B1 degradation when cells enter anaphase, under control of the spindle assembly checkpoint (SAC) (Musacchio, 2015). This allows the dephosphorylation of Cdk substrates by PP1/PP2A phosphatases, setting the time for chromosome decondensation and nuclear envelope reformation (NER) (Wurzenberger and Gerlich, 2011), two hallmarks of mitotic exit. This model is supported by the observation that inhibition of PP1/PP2A or Afonso et al eLife 2019;8:e47646.
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