Hyperactivation of cyclin A-CDK induces centrosome overduplication and chromosome tetraploidization in mouse cells.

Tetsuo Niwa, Yasunori Akaike, Kaichi Watanabe, Taku Chibazakura

Biochemical and biophysical research communications 2021 Apr 16

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Mammalian cyclin A-CDK (cyclin-dependent kinase) activity during mitotic exit is regulated by two redundant pathways, cyclin degradation and CDK inhibitors (CKIs). Ectopic expression of a destruction box-truncated (thereby stabilized) mutant of cyclin A in the mouse embryonic fibroblasts nullizygous for three CKIs (p21, p27, and p107) results in constitutive activation ("hyperactivation") of cyclin A-CDK and induces rapid tetraploidization, suggesting loss of the two redundant pathways causes genomic instability. To elucidate the mechanism underlying teraploidization by hyperactive cyclin A-CDK, we first examined if the induction of tetraploidization depends on specific cell cycle stage(s). Arresting the cell cycle at either S phase or M phase blocked the induction of tetraploidization, which was restored by subsequent release from the arrest. These results suggest that both S- and M-phase progressions are necessary for the tetraploidization by hyperactive cyclin A-CDK and that the tetraploidization is not caused by chromosome endoreduplication but by mitotic failure. We also observed that the induction of tetraploidization is associated with excessive duplication of centrosomes, which was suppressed by S-phase but not M-phase block, suggesting that hyperactive cyclin A-CDK promotes centrosome overduplication during S phase. Time-lapse microscopy revealed that hyperactive cyclin A-CDK can lead cells to bypass cell division and enter pseudo-G1 state. These observations implicate that hyperactive cyclin A-CDK causes centrosome overduplication, which leads to mitotic slippage and subsequent tetraploidization. Copyright © 2021 Elsevier Inc. All rights reserved.

Citation

Tetsuo Niwa, Yasunori Akaike, Kaichi Watanabe, Taku Chibazakura. Hyperactivation of cyclin A-CDK induces centrosome overduplication and chromosome tetraploidization in mouse cells. Biochemical and biophysical research communications. 2021 Apr 16;549:91-97