MCM9 Is Required for Mammalian DNA Mismatch Repair

Sabine Traver; Philippe Coulombe; Isabelle Peiffer; James R A Hutchins; Magali Kitzmann; Daniel Latreille; Marcel Méchali

doi:10.1016/j.molcel.2015.07.010

MCM9 Is Required for Mammalian DNA Mismatch Repair

Mol Cell. 2015 Sep 3;59(5):831-9. doi: 10.1016/j.molcel.2015.07.010. Epub 2015 Aug 20.

Authors

Sabine Traver¹, Philippe Coulombe¹, Isabelle Peiffer¹, James R A Hutchins¹, Magali Kitzmann¹, Daniel Latreille², Marcel Méchali³

Affiliations

¹ Laboratory of DNA Replication and Genome Dynamics, Institute of Human Genetics, CNRS, 141 rue de la Cardonille, 34396 Montpellier, France.
² Laboratory of Gene Regulation, Institute of Human Genetics, CNRS, 141 rue de la Cardonille, 34396 Montpellier, France.
³ Laboratory of DNA Replication and Genome Dynamics, Institute of Human Genetics, CNRS, 141 rue de la Cardonille, 34396 Montpellier, France. Electronic address: mechali@igh.cnrs.fr.

PMID: 26300262
DOI: 10.1016/j.molcel.2015.07.010

Abstract

DNA mismatch repair (MMR) is an evolutionarily conserved process that corrects DNA polymerase errors during replication to maintain genomic integrity. In E. coli, the DNA helicase UvrD is implicated in MMR, yet an analogous helicase activity has not been identified in eukaryotes. Here, we show that mammalian MCM9, a protein involved in replication and homologous recombination, forms a complex with MMR initiation proteins (MSH2, MSH3, MLH1, PMS1, and the clamp loader RFC) and is essential for MMR. Mcm9-/- cells display microsatellite instability and MMR deficiency. The MCM9 complex has a helicase activity that is required for efficient MMR since wild-type but not helicase-dead MCM9 restores MMR activity in Mcm9-/- cells. Moreover, MCM9 loading onto chromatin is MSH2-dependent, and in turn MCM9 stimulates the recruitment of MLH1 to chromatin. Our results reveal a role for MCM9 and its helicase activity in mammalian MMR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / chemistry
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Base Sequence
Chromatin / genetics
Chromatin / metabolism
DNA / genetics
DNA / metabolism
DNA Helicases / chemistry
DNA Helicases / genetics
DNA Helicases / metabolism
DNA Mismatch Repair / genetics
DNA Mismatch Repair / physiology*
DNA-Binding Proteins / chemistry
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Gene Knockout Techniques
HeLa Cells
Humans
Microsatellite Instability
Minichromosome Maintenance Proteins / deficiency
Minichromosome Maintenance Proteins / genetics
Minichromosome Maintenance Proteins / metabolism*
MutL Protein Homolog 1
MutS Homolog 2 Protein / chemistry
MutS Homolog 2 Protein / genetics
MutS Homolog 2 Protein / metabolism
MutS Homolog 3 Protein
Nuclear Proteins / chemistry
Nuclear Proteins / genetics
Nuclear Proteins / metabolism

Substances

Adaptor Proteins, Signal Transducing
Chromatin
DNA-Binding Proteins
MLH1 protein, human
MSH3 protein, human
MutS Homolog 3 Protein
Nuclear Proteins
DNA
MSH2 protein, human
MutL Protein Homolog 1
MutS Homolog 2 Protein
DNA Helicases
MCM9 protein, human
Minichromosome Maintenance Proteins