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Molecular and Cellular Biology, August 2005, p. 6707-6721, Vol. 25, No. 15
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.15.6707-6721.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Disruption of Mechanisms That Prevent Rereplication Triggers a DNA Damage Response{dagger}

Vincent Archambault,{ddagger} Amy E. Ikui,{ddagger} Benjamin J. Drapkin, and Frederick R. Cross*

The Rockefeller University, New York, New York 10021

Received 21 September 2004/ Returned for modification 29 November 2004/ Accepted 4 May 2005

Eukaryotes replicate DNA once and only once per cell cycle due to multiple, partially overlapping mechanisms efficiently preventing reinitiation. The consequences of reinitiation are unknown. Here we show that the induction of rereplication by mutations in components of the prereplicative complex (origin recognition complex [ORC], Cdc6, and minichromosome maintenance proteins) causes a cell cycle arrest with activated Rad53, a large-budded morphology, and an undivided nucleus. Combining a mutation disrupting the Clb5-Orc6 interaction (ORC6-rxl) and a mutation stabilizing Cdc6 (CDC6{Delta}NT) causes a cell cycle delay with a similar phenotype, although this background is only partially compromised for rereplication control and does not exhibit overreplication detectable by fluorescence-activated cell sorting. We conducted a systematic screen that identified genetic requirements for the viability of these cells. ORC6-rxl CDC6{Delta}NT cells depend heavily on genes required for the DNA damage response and for double-strand-break repair by homologous recombination. Our results implicate an Mre11-Mec1-dependent pathway in limiting the extent of rereplication.

* Corresponding author. Mailing address: The Rockefeller University, 1230 York Ave., Box 237, New York, NY 10021. Phone: (212) 327-7685. Fax: (212) 327-7193. E-mail: fcross{at}rockefeller.edu.

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

{ddagger} These authors contributed equally to this work.

Molecular and Cellular Biology, August 2005, p. 6707-6721, Vol. 25, No. 15
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.15.6707-6721.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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