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

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


  • Kan Q
  • Jinno S
  • Yamamoto H
  • Kobayashi K
  • Okayama H


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

March 25, 2008

Associated Grants


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