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bioRxiv · 10.1101/2023.05.19.541462

The oscillation of mitotic kinase governs cell cycle latches in mammalian cells

Dragoi, C.-M.·Barr, A. R.·Tyson, J. J.·Novak, B.
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Abstract

The mammalian cell cycle alternates between two phases: S-G2-M with high levels of A- and B-type cyclin-dependent kinases (CycA,B:CDK); and G1 with persistent degradation of CycA,B by Cdh1-activated APC/C (anaphase promoting complex/cyclosome). Because CDKs phosphorylate and inactivate Cdh1, these two phases are mutually exclusive. This toggle switch is flipped from G1 to S by cyclin-E (CycE:CDK), which is not degraded by Cdh1:APC/C; and from M to G1 by Cdc20:APC/C, which is not inactivated by CycA,B:CDK. After flipping the switch, cyclin E is degraded and Cdc20:APC/C is inactivated. Combining mathematical modelling with single-cell timelapse imaging, we show that dysregulation of CycB:CDK disrupts strict alternation of the G1-S and M-G1 switches. Inhibition of CycB:CDK results in Cdc20-independent Cdh1 endocycles, and sustained activity of CycB:CDK drives Cdh1-independent Cdc20 endocycles. Our model provides one mechanistic explanation for how whole genome doubling can arise, a common event in tumorigenesis that can drive tumour evolution.

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Dragoi, C.-M., Barr, A. R., Tyson, J. J., Novak, B.. 2023-05-22. The oscillation of mitotic kinase governs cell cycle latches in mammalian cells. https://doi.org/10.1101/2023.05.19.541462

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