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ATP-dependent activation of p21WAF1/CIP1-associated Cdk2 by Cdc6.

http://www.ncbi.nlm.nih.gov/pubmed/18356301

When cells progressing in mid-S phase are damaged with a base-modifying chemical, they arrest in S phase long after the CHK1 checkpoint signal fades out, partly because of p53-mediated long-lasting induction of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1). We have recently found that enforced expression of Cdc6, the assembler of prereplicative complexes, markedly advances recovery from the prolonged S-phase arrest and reactivation of Cdk2 despite the presence of a high level of induced p21. Here, we report that Cdc6 protein can activate p21-associated Cdk2 in an ATP-dependent manner in vitro. Consistently, Cdc6 mutated for ATPase or a putative cyclin binding motif is no longer able to activate the Cdk2 in vitro or promote reinitiation of S-phase progression and reactivation of Cdk2 in vivo. These results reveal the never anticipated function of Cdc6 and redefine its role in the control of S-phase progression in mammalian cells.

Pubmed ID: 18356301 RIS Download

Mesh terms: Adenosine Triphosphatases | Adenosine Triphosphate | Amino Acid Motifs | Animals | Cell Cycle Proteins | Chromosomal Proteins, Non-Histone | Cyclin-Dependent Kinase 2 | Cyclin-Dependent Kinase Inhibitor p21 | Cyclin-Dependent Kinase Inhibitor p27 | Cyclins | Enzyme Activation | Methyl Methanesulfonate | Mice | Mutation | Protein Binding | Rats | S Phase

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