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

• Published in: Journal of cell science Vol. 137; no. 3
• Main Authors: Dragoi, Calin-Mihai, Kaur, Ekjot, Barr, Alexis R., Tyson, John J., Novák, Béla
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01.02.2024
• Subjects: Anaphase-Promoting Complex-Cyclosome - metabolism; Animals; Cdc20 Proteins - metabolism; Cell Cycle; Cell Cycle Proteins - metabolism; Cyclin-Dependent Kinases - metabolism; Cyclins; Mammals - metabolism; Mitosis; Endocycles; Biochemical switches; Size control; Hysteresis; Bistability
• ISSN: 0021-9533; 1477-9137; 1477-9137
• DOI: 10.1242/jcs.261364

The mammalian cell cycle alternates between two phases – S-G2-M with high levels of A- and B-type cyclins (CycA and CycB, respectively) bound to cyclin-dependent kinases (CDKs), and G1 with persistent degradation of CycA and CycB by an activated anaphase promoting complex/cyclosome (APC/C) bound to Cdh1 (also known as FZR1 in mammals; denoted APC/C:Cdh1). Because CDKs phosphorylate and inactivate Cdh1, these two phases are mutually exclusive. This ‘toggle switch’ is flipped from G1 to S by cyclin-E bound to a CDK (CycE:CDK), which is not degraded by APC/C:Cdh1, and from M to G1 by Cdc20-bound APC/C (APC/C:Cdc20), which is not inactivated by CycA:CDK or CycB:CDK. After flipping the switch, cyclin E is degraded and APC/C:Cdc20 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 a mechanistic explanation for how whole-genome doubling can arise, a common event in tumorigenesis that can drive tumour evolution.