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Vol. 17, Issue 5, 2401-2414, May 2006

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Genome-wide Mapping of DNA Synthesis in Saccharomyces cerevisiae Reveals That Mechanisms Preventing Reinitiation of DNA Replication Are Not Redundant

Brian M. Green ^* , Richard J. Morreale ^* , Bilge Özaydin , Joseph L. DeRisi ^*, and Joachim J. Li 

^* Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143-2200; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143-2200; and Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720

Submitted November 14, 2005; Revised February 7, 2006; Accepted February 8, 2006
Monitoring Editor: Orna Cohen-Fix

To maintain genomic stability, reinitiation of eukaryotic DNA replication within a single cell cycle is blocked by multiple mechanisms that inactivate or remove replication proteins after G1 phase. Consistent with the prevailing notion that these mechanisms are redundant, we previously showed that simultaneous deregulation of three replication proteins, ORC, Cdc6, and Mcm2-7, was necessary to cause detectable bulk re-replication in G2/M phase in Saccharomyces cerevisiae. In this study, we used microarray comparative genomic hybridization (CGH) to provide a more comprehensive and detailed analysis of re-replication. This genome-wide analysis suggests that reinitiation in G2/M phase primarily occurs at a subset of both active and latent origins, but is independent of chromosomal determinants that specify the use and timing of these origins in S phase. We demonstrate that re-replication can be induced within S phase, but differs in amount and location from re-replication in G2/M phase, illustrating the dynamic nature of DNA replication controls. Finally, we show that very limited re-replication can be detected by microarray CGH when only two replication proteins are deregulated, suggesting that the mechanisms blocking re-replication are not redundant. Therefore we propose that eukaryotic re-replication at levels below current detection limits may be more prevalent and a greater source of genomic instability than previously appreciated.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

These authors contributed equally to this work.

Address correspondence to: Joachim J. Li (joachim.li{at}ucsf.edu).

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