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Molecular and Cellular Biology, September 2007, p. 6396-6406, Vol. 27, No. 18
0270-7306/07/$08.00+0     doi:10.1128/MCB.00719-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Replication in Hydroxyurea: It's a Matter of Time{triangledown} ,{dagger}

Gina M. Alvino,1 David Collingwood,2 John M. Murphy,1 Jeffrey Delrow,3 Bonita J. Brewer,1 and M. K. Raghuraman1*

Department of Genome Sciences, University of Washington, Seattle, Washington 98195,1 Department of Mathematics, University of Washington, Seattle, Washington 98195,2 Department of Genomic Resources, Fred Hutchinson Cancer Research Center, Seattle, Washington 981093

Received 24 April 2007/ Returned for modification 11 June 2007/ Accepted 9 July 2007

Hydroxyurea (HU) is a DNA replication inhibitor that negatively affects both the elongation and initiation phases of replication and triggers the "intra-S phase checkpoint." Previous work with budding yeast has shown that, during a short exposure to HU, MEC1/RAD53 prevent initiation at some late S phase origins. In this study, we have performed microarray experiments to follow the fate of all origins over an extended exposure to HU. We show that the genome-wide progression of DNA synthesis, including origin activation, follows the same pattern in the presence of HU as in its absence, although the time frames are very different. We find no evidence for a specific effect that excludes initiation from late origins. Rather, HU causes S phase to proceed in slow motion; all temporal classes of origins are affected, but the order in which they become active is maintained. We propose a revised model for the checkpoint response to HU that accounts for the continued but slowed pace of the temporal program of origin activation.

* Corresponding author. Mailing address: Department of Genome Sciences, University of Washington, Seattle, WA 98195. Phone: (206) 543-0334. Fax: (206) 685-7301. E-mail: raghu{at}u.washington.edu

{triangledown} Published ahead of print on 16 June 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, September 2007, p. 6396-6406, Vol. 27, No. 18
0270-7306/07/$08.00+0     doi:10.1128/MCB.00719-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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