MCM9 Is Required for Mammalian DNA Mismatch Repair

Sabine Traver (1, 2, 3) , Philippe Coulombe (2) , Isabelle Peiffer (2) , James R. A. Hutchins (2) , Magali Kitzmann (2) , Daniel Latreille (2) , Marcel Méchali (2)

1 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
2 IGH - Institut de génétique humaine
3 UMR 1203 - Développement embryonnaire précoce humain et pluripotence EmbryoPluripotency

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.

Domaines: Biologie cellulaire

Sabine Traver, Philippe Coulombe, Isabelle Peiffer, James R. A. Hutchins, Magali Kitzmann, et al.. MCM9 Is Required for Mammalian DNA Mismatch Repair. Molecular Cell, 2015, 59 (5), pp.831-839. ⟨10.1016/j.molcel.2015.07.010⟩. ⟨hal-02361154⟩