title: MCM9 Is Required for Mammalian DNA Mismatch Repair.
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.
authors: Laboratory of DNA Replication and Genome Dynamics, Institute of Human Genetics, CNRS, 141 rue de la Cardonille, 34396 Montpellier, France.
authors: Sabine
authors: S
authors: Traver
authors: Laboratory of DNA Replication and Genome Dynamics, Institute of Human Genetics, CNRS, 141 rue de la Cardonille, 34396 Montpellier, France.
authors: Philippe
authors: P
authors: Coulombe
authors: Laboratory of DNA Replication and Genome Dynamics, Institute of Human Genetics, CNRS, 141 rue de la Cardonille, 34396 Montpellier, France.
authors: Isabelle
authors: I
authors: Peiffer
authors: Laboratory of DNA Replication and Genome Dynamics, Institute of Human Genetics, CNRS, 141 rue de la Cardonille, 34396 Montpellier, France.
authors: James R A
authors: JR
authors: Hutchins
authors: Laboratory of DNA Replication and Genome Dynamics, Institute of Human Genetics, CNRS, 141 rue de la Cardonille, 34396 Montpellier, France.
authors: Magali
authors: M
authors: Kitzmann
authors: Laboratory of Gene Regulation, Institute of Human Genetics, CNRS, 141 rue de la Cardonille, 34396 Montpellier, France.
authors: Daniel
authors: D
authors: Latreille
authors: 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.
authors: Marcel
authors: M
authors: Méchali
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053843:DNA Mismatch Repair / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055786:Gene Knockout Techniques; D006367:HeLa Cells; D006801:Humans; D053842:Microsatellite Instability; D064110:Minichromosome Maintenance Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000074081:MutS Homolog 3 Protein; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002843:Chromatin; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; C078444:MSH3 protein, human; D000074081:MutS Homolog 3 Protein; D009687:Nuclear Proteins; D004247:DNA; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D004265:DNA Helicases; C501931:MCM9 protein, human; D064110:Minichromosome Maintenance Proteins