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Phosphorylation-dependent binding of mitotic cyclins to Cdc6 contributes to DNA replication control

Author

Listed:
  • Satoru Mimura

    (Cancer Research UK London Research Institute, Clare Hall Laboratories)

  • Takashi Seki

    (Cancer Research UK London Research Institute, Clare Hall Laboratories
    Nagoya University)

  • Seiji Tanaka

    (Cancer Research UK London Research Institute, Clare Hall Laboratories
    National Institute of Genetics, Division of Microbial Genetics)

  • John F. X. Diffley

    (Cancer Research UK London Research Institute, Clare Hall Laboratories)

Abstract

Cyclin-dependent kinases (CDKs) limit the activation of DNA replication origins to once per cell cycle by preventing the assembly of pre-replicative complexes (pre-RCs) during S, G2 and M phases of the cell cycle in the budding yeast Saccharomyces cerevisiae1,2. CDKs inhibit each pre-RC component (ORC, Cdc6, Cdt1/Mcm2-7) by different mechanisms. We show here that the mitotic CDK, Clb2/Cdc28, binds tightly to an amino-terminal domain (NTD) of Cdc6, and that Cdc6 in this complex is unable to assemble pre-RCs. We present evidence indicating that this Clb2-dependent mechanism contributes to preventing re-replication in vivo. CDK interaction with the NTD of Cdc6 is mediated by the cyclin subunit Clb2, and could be reconstituted with recombinant Clb2 protein and synthetic NTD peptides. Tight Clb2 binding occurred only when the NTD was phosphorylated on CDK consensus sites. Human CDKs containing cyclins A, B and E also bound specifically to phospho-NTD peptides. We propose that direct binding of cyclins to phosphopeptide motifs may be a widespread phenomenon contributing to the targeting of CDKs to substrates.

Suggested Citation

  • Satoru Mimura & Takashi Seki & Seiji Tanaka & John F. X. Diffley, 2004. "Phosphorylation-dependent binding of mitotic cyclins to Cdc6 contributes to DNA replication control," Nature, Nature, vol. 431(7012), pages 1118-1123, October.
    • Handle: RePEc:nat:nature:v:431:y:2004:i:7012:d:10.1038_nature03024
    DOI: 10.1038/nature03024
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