Linker domain function predicts pathogenic MLH1 missense variants

Proc Natl Acad Sci U S A. 2021 Mar 2;118(9):e2019215118. doi: 10.1073/pnas.2019215118.

Abstract

The pathogenic consequences of 369 unique human HsMLH1 missense variants has been hampered by the lack of a detailed function in mismatch repair (MMR). Here single-molecule images show that HsMSH2-HsMSH6 provides a platform for HsMLH1-HsPMS2 to form a stable sliding clamp on mismatched DNA. The mechanics of sliding clamp progression solves a significant operational puzzle in MMR and provides explicit predictions for the distribution of clinically relevant HsMLH1 missense mutations.

Keywords: HNPCC; Lynch syndrome; mismatch repair; single molecule; sliding clamp.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / metabolism
  • Colorectal Neoplasms, Hereditary Nonpolyposis / pathology
  • DNA / chemistry
  • DNA / genetics*
  • DNA / metabolism
  • DNA Damage
  • DNA Mismatch Repair*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Humans
  • Models, Molecular
  • MutL Protein Homolog 1 / chemistry
  • MutL Protein Homolog 1 / genetics*
  • MutL Protein Homolog 1 / metabolism
  • MutS Homolog 2 Protein / chemistry
  • MutS Homolog 2 Protein / genetics*
  • MutS Homolog 2 Protein / metabolism
  • Mutation, Missense*
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs

Substances

  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • MLH1 protein, human
  • DNA
  • MSH2 protein, human
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein