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A more recent version of this article appeared on December 1, 2008
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Submitted on June 24, 2008
Revised on August 28, 2008
Accepted on September 8, 2008
*Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605; Department of Molecular Genetics and Microbiology, State University of New York, Stony Brook, NY 11794; Genomes Stability Unit, Pasteur Institute, 75724 Paris, France; ||Department of Physics, Simon Fraser University, Burnaby, BC, Canada V5A 1S6
Monitoring Editor: Daniel J. Lew
Origins of DNA replication are generally inefficient, with most firing in fewer than half of cell cycles. However, neither the mechanism nor the importance of the regulation of origin efficiency is clear. In fission yeast, origin firing is stochastic, leading us to hypothesize that origin inefficiency and stochasticity are the result of a diffusible, rate-limiting activator. We show that the Hsk1-Dfp1 replication kinase (the fission yeast Cdc7-Dbf4 homolog) plays such a role. Increasing or decreasing Hsk1-Dfp1 levels correspondingly increases or decreases origin efficiency. Furthermore, tethering Hsk1-Dfp1 near an origin increases the efficiency of that origin, suggesting that the effective local concentration of Hsk1-Dfp1 regulates origin firing. Using photobleaching, we show that Hsk1-Dfp1 is freely diffusible in the nucleus. These results support a model in which the accessibility of replication origins to Hsk1-Dfp1 regulates origin efficiency and provides a potential mechanistic link between chromatin structure and replication timing. By manipulating Hsk1-Dfp1 levels, we show that increasing or decreasing origin firing rates leads to an increase in genomic instability, demonstrating the biological importance of appropriate origin efficiency.
Present address: Genomic Vision, Paris Santé Cochin, 29 rue du Faubourg Saint Jacques, 75014 Paris, France.
Address correspondence to:
Nicholas Rhind (nick.rhind{at}umassmed.edu)
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