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Cyclin-dependent kinases prevent DNA re-replication through multiple mechanisms

Author

Listed:
  • Van Q. Nguyen

    (Department of Biochemistry and Biophysics)

  • Carl Co

    (Department of Biochemistry and Biophysics)

  • Joachim J. Li

    (University of California)

Abstract

The stable propagation of genetic information requires that the entire genome of an organism be faithfully replicated once and only once each cell cycle. In eukaryotes, this replication is initiated at hundreds to thousands of replication origins distributed over the genome, each of which must be prohibited from re-initiating DNA replication within every cell cycle. How cells prevent re-initiation has been a long-standing question in cell biology. In several eukaryotes, cyclin-dependent kinases (CDKs) have been implicated in promoting the block to re-initiation1, but exactly how they perform this function is unclear. Here we show that B-type CDKs in Saccharomyces cerevisiae prevent re-initiation through multiple overlapping mechanisms, including phosphorylation of the origin recognition complex (ORC), downregulation of Cdc6 activity, and nuclear exclusion of the Mcm2-7 complex. Only when all three inhibitory pathways are disrupted do origins re-initiate DNA replication in G2/M cells. These studies show that each of these three independent mechanisms of regulation is functionally important.

Suggested Citation

  • Van Q. Nguyen & Carl Co & Joachim J. Li, 2001. "Cyclin-dependent kinases prevent DNA re-replication through multiple mechanisms," Nature, Nature, vol. 411(6841), pages 1068-1073, June.
    • Handle: RePEc:nat:nature:v:411:y:2001:i:6841:d:10.1038_35082600
    DOI: 10.1038/35082600
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    Cited by:

    1. Aftab Amin & Cheung Man Hei & Chun Liang & Aftab Amin & Cheung Man Hei & Chun Liang & Chun Liang & Aftab Amin & Cheung Man Hei & Chun Liang, 2019. "DNA Replication-Initiation Proteins in Eukaryotic Cells," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 22(5), pages 17042-17049, December.
    2. Jan Marten Schmidt & Ran Yang & Ashish Kumar & Olivia Hunker & Jan Seebacher & Franziska Bleichert, 2022. "A mechanism of origin licensing control through autoinhibition of S. cerevisiae ORC·DNA·Cdc6," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Anneke Brümmer & Carlos Salazar & Vittoria Zinzalla & Lilia Alberghina & Thomas Höfer, 2010. "Mathematical Modelling of DNA Replication Reveals a Trade-off between Coherence of Origin Activation and Robustness against Rereplication," PLOS Computational Biology, Public Library of Science, vol. 6(5), pages 1-13, May.
    4. Karl-Uwe Reusswig & Julia Bittmann & Martina Peritore & Mathilde Courtes & Benjamin Pardo & Michael Wierer & Matthias Mann & Boris Pfander, 2022. "Unscheduled DNA replication in G1 causes genome instability and damage signatures indicative of replication collisions," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    5. Yue Wu & Qiongdan Zhang & Yuhan Lin & Wai Hei Lam & Yuanliang Zhai, 2024. "Replication licensing regulated by a short linear motif within an intrinsically disordered region of origin recognition complex," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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