“Control of Cell Proliferation by Memories of Mitosis”, 2022-11-16 ():
Time spent in mitosis is carefully monitored to halt the proliferation of potentially dangerous cells in a population.
Mitotic duration is tightly constrained, with extended mitotic duration being a characteristic of potentially problematic cells prone to chromosome missegregation and genomic instability.
We show that memories of mitotic duration are integrated by a p53-based mitotic stopwatch pathway to exert tight control over proliferation. The stopwatch halts proliferation of the products of a single extended mitosis or of successive modestly extended mitoses. Time in mitosis is monitored via mitotic kinase-regulated assembly of stopwatch complexes that are transmitted to daughter cells.
The stopwatch is inactivated in p53-mutant cancers, as well as in a substantial proportion of p53-wildtype cancers, consistent with classification of stopwatch complex subunits as tumor suppressors. Stopwatch status additionally influences efficacy of anti-mitotic agents currently used or in development for cancer therapy.