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Minichromosome Maintenance Proteins Interact with Checkpoint and Recombination Proteins To Promote S-Phase Genome Stability ^,

Julie M. Bailis,^1, Douglas D. Luche,² Tony Hunter,¹ and Susan L. Forsburg^1,2*

Molecular and Cell Biology Laboratory, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037,¹ Molecular and Computational Biology Section, University of Southern California, 1050 Childs Way RRI 201B, Los Angeles, California 90089-2910²

Received 18 September 2007/ Returned for modification 19 October 2007/ Accepted 19 December 2007

The minichromosome maintenance (MCM) complex plays essential, conserved roles throughout DNA synthesis: first, as a component of the prereplication complex at origins and, then, as a helicase associated with replication forks. Here we use fission yeast (Schizosaccharomyces pombe) as a model to demonstrate a role for the MCM complex in protecting replication fork structure and promoting recovery from replication arrest. Loss of MCM function generates lethal double-strand breaks at sites of DNA synthesis during replication elongation, suggesting replication fork collapse. MCM function also maintains the stability of forks stalled by hydroxyurea that activate the replication checkpoint. In cells where the checkpoint is activated, Mcm4 binds the Cds1 kinase and undergoes Cds1-dependent phosphorylation. MCM proteins also interact with proteins involved in homologous recombination, which promotes recovery from arrest by ensuring normal mitosis. We suggest that the MCM complex links replication fork stabilization with checkpoint arrest and recovery through direct interactions with checkpoint and recombination proteins and that this role in S-phase genome stability is conserved from yeast to human cells.

Published ahead of print on 7 January 2008.

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

Present address: Amgen, 1201 Amgen Court West, Seattle, WA 98119.