Abstract
The activation of phase-specific cyclin-dependent kinases (Cdks) is associated with ordered cell cycle transitions. Among the mammalian Cdks, only Cdk1 is essential for somatic cell proliferation. Cdk1 can apparently substitute for Cdk2, Cdk4, and Cdk6, which are individually dispensable in mice. It is unclear if all functions of non-essential Cdks are fully redundant with Cdk1. Using a genetic approach, we show that Cdk2, the S-phase Cdk, uniquely controls the G2/M checkpoint that prevents cells with damaged DNA from initiating mitosis. CDK2-nullizygous human cells exposed to ionizing radiation failed to exclude Cdk1 from the nucleus and exhibited a marked defect in G2/M arrest that was unmasked by the disruption of P53. The DNA replication licensing protein Cdc6, which is normally stabilized by Cdk2, was physically associated with the checkpoint regulator ATR and was required for efficient ATR-Chk1-Cdc25A signaling. These findings demonstrate that Cdk2 maintains a balance of S-phase regulatory proteins and thereby coordinates subsequent p53-independent G2/M checkpoint activation.
Highlights
cyclin-dependent kinases (Cdks) associate with cyclins to form heterodimers that are sequentially activated during the cell cycle
Stabilization of Cdc25A in Cdk2-deficient cells Does Cdk2 contribute to human checkpoints? We first tested whether Cdk2 is required for the regulation of Cdc25A, a common target of checkpoint kinases and a critical mediator of cell cycle transitions
Our study demonstrates that Cdk2 is required for robust DNA damage checkpoint signaling
Summary
Cdks associate with cyclins to form heterodimers that are sequentially activated during the cell cycle. Metazoan cells have multiple Cdks and cyclins that are temporally regulated [1,2]. Cdk and Cdk pair with D-type cyclins during G1, Cdk pairs with E- and A-type cyclins during S and G2, and Cdk pairs with A- and B-type cyclins during G2 and M. RNAi-mediated depletion of Cdks in human cells [6] and gene knockouts in mice [7,8,9,10] showed that Cdk, Cdk and Cdk are dispensable for cell cycle progression. Cdk can bind D-, E-, and A-type cyclins and functionally substitute for the non-essential Cdks [11]. While it is clear that Cdk alone can drive unperturbed cell cycle progression, it remains unclear whether the non-essential Cdks have non-redundant functions in cell cycle responses to stress
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