MCM proteins interact with checkpoint and recombination proteins to promote S phase genome stability

Molecular and Cell Biology Laboratory, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037; Molecular and Computational Biology Section, University of Southern California, 1050 Childs Way RRI 201B, Los Angeles, CA 90089-2910

^* To whom correspondence should be addressed. Email: forsburg{at}usc.edu.

	Abstract

The MCM complex plays an essential, conserved role throughout DNA synthesis: first, as a component of the pre-replication complex at origins, and then as a helicase associated with replication forks. Here, we use fission yeast 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 promote 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.