Minichromosome maintenance proteins interact with checkpoint and recombination proteins to promote s-phase genome stability.

Abstract	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.
Authors	Julie M Bailis, Douglas D Luche, Tony Hunter, Susan L Forsburg
Journal	Molecular and cellular biology (Mol Cell Biol) Vol. 28 Issue 5 Pg. 1724-38 (Mar 2008) ISSN: 1098-5549 [Electronic] United States
PMID	18180284 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Cell Cycle Proteins DNA-Binding Proteins Mutagens Nucleic Acid Synthesis Inhibitors RHP51 protein, S pombe RNA, Small Interfering Schizosaccharomyces pombe Proteins Bleomycin Proline Methyl Methanesulfonate Protein Kinases Checkpoint Kinase 2 CHEK2 protein, human Cds1 protein, S pombe Protein Serine-Threonine Kinases rad3 protein, S pombe Rad51 Recombinase Minichromosome Maintenance Complex Component 4 mcm4 protein, S pombe Hydroxyurea
Topics	Amino Acid Substitution Bleomycin (pharmacology) Cell Cycle Proteins (genetics, metabolism) Cell Survival (drug effects) Checkpoint Kinase 2 DNA Damage DNA-Binding Proteins (genetics, metabolism) Gamma Rays Genomic Instability HeLa Cells Humans Hydroxyurea (pharmacology) Methyl Methanesulfonate (pharmacology) Minichromosome Maintenance Complex Component 4 Mutagens (pharmacology) Nucleic Acid Synthesis Inhibitors (pharmacology) Phosphorylation Proline (metabolism) Protein Kinases (metabolism) Protein Serine-Threonine Kinases (metabolism) RNA, Small Interfering (metabolism) Rad51 Recombinase (metabolism) Recombination, Genetic S Phase Schizosaccharomyces (genetics) Schizosaccharomyces pombe Proteins (genetics, metabolism) Temperature Time Factors Transfection

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