Structure of the MutLα C-terminal Domain Reveals How Mlh1 Contributes to Pms1 Endonuclease Site

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2013 Feb 26

PMID 23435383

Citations 74

Authors

Emeric Gueneau

Claudine DHerin

Pierre Legrand

Carine Tellier-Lebegue

Bernard Gilquin

Pierre Bonnesoeur

Floriana Londino

Cathy Quemener

Marie-Helene Le Du

Josan A Marquez

Mireille Moutiez

Muriel Gondry

Serge Boiteux

Jean-Baptiste Charbonnier

Affiliations

Soon will be listed here.

Abstract

Mismatch-repair factors have a prominent role in surveying eukaryotic DNA-replication fidelity and in ensuring correct meiotic recombination. These functions depend on MutL-homolog heterodimers with Mlh1. In humans, MLH1 mutations underlie half of hereditary nonpolyposis colorectal cancers (HNPCCs). Here we report crystal structures of the MutLα (Mlh1-Pms1 heterodimer) C-terminal domain (CTD) from Saccharomyces cerevisiae, alone and in complex with fragments derived from Mlh1 partners. These structures reveal structural rearrangements and additional domains in MutLα as compared to the bacterial MutL counterparts and show that the strictly conserved C terminus of Mlh1 forms part of the Pms1 endonuclease site. The structures of the ternary complexes between MutLα(CTD) and Exo1 or Ntg2 fragments reveal the binding mode of the MIP-box motif shared by several Mlh1 partners. Finally, the structures provide a rationale for the deleterious impact of MLH1 mutations in HNPCCs.

Citing Articles

The mismatch repair factor Mlh1-Pms1 uses ATP to compact and remodel DNA.

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Mlh1-Pms1 ATPase activity is regulated distinctly by self-generated nicks and strand discrimination signals in mismatch repair.

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Combining single-molecule and structural studies reveals protein and DNA conformations and assemblies that govern DNA mismatch repair.

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The Mlh1-Pms1 endonuclease uses ATP to preserve DNA discontinuities as strand discrimination signals to facilitate mismatch repair.

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