Dna damage induces chk1-dependent threonine-160 phosphorylation and activation of cdk2

Bourke, E
Brown, J A L
Takeda, S
Hochegger, H
Morrison, C G
Bourke, E; Brown, J A L; Takeda, S; Hochegger, H; Morrison, C G (2009). Dna damage induces chk1-dependent threonine-160 phosphorylation and activation of cdk2. Oncogene 29 (4), 616-624
Abnormal centrosome numbers arise in tumours and can cause multipolar mitoses and genome instability. Cdk2 controls normal centrosome duplication, but Chk1-dependent centrosome amplification also occurs after DNA damage. We investigated the involvement of cyclin-dependent kinases (Cdks) in DNA damage-induced centrosome amplification using cells lacking either Cdk2, or both Cdk1 and Cdk2 activity. Cdk2(-/-) DT40 cells showed robust centrosome amplification after ionizing radiation (IR), whereas Cdk1-deficient Cdk2(-/-) cells showed no centrosome amplification, demonstrating that Cdk1 can substitute for Cdk2 in this pathway. Surprisingly, we found that Cdk2 activity was upregulated by IR in wild-type but not in Chk1(-/-) DT40 cells. Cdk2 upregulation also occurred in HeLa cells after IR treatment. Chk1-dependent Cdk2 induction was not accompanied by increased levels of Cdk1, Cdk2, cyclin A or cyclin E, but activating T160 phosphorylation of Cdk2 increased after IR. Moreover, Cdk2 overexpression restored IR-induced centrosome amplification in Cdk1-deficient Cdk2(-/-) cells, but T160A mutation blocked this rescue. Our data suggest that Chk1 signalling causes centrosome amplification after IR by upregulating Cdk2 activity through activating phosphorylation. Oncogene (2010) 29, 616-624; doi: 10.1038/onc.2009.340; published online 19 October 2009
Springer Nature
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