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.
Copyright © 2021 the Author(s). Published by PNAS.
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