hMSH2-hMSH6 forms a hydrolysis-independent sliding clamp on mismatched DNA

Mol Cell. 1999 Feb;3(2):255-61. doi: 10.1016/s1097-2765(00)80316-0.


Mismatch recognition by the human MutS homologs hMSH2-hMSH6 is regulated by adenosine nucleotide binding, supporting the hypothesis that it functions as a molecular switch. Here we show that ATP-induced release of hMSH2-hMSH6 from mismatched DNA is prevented if the ends are blocked or if the DNA is circular. We demonstrate that mismmatched DNA provokes ADP-->ATP exchange, resulting in a discernible conformational transition that converts hMSH2-hMSH6 into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone. Our results support a model for bidirectional mismatch repair in which stochastic loading of multiple ATP-bound hMSH2-hMSH6 sliding clamps onto mismatch-containing DNA leads to activation of the repair machinery and/or other signaling effectors similar to G protein switches.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphatases*
  • Adenosine Triphosphate / physiology
  • Bacterial Proteins / physiology
  • Base Pairing
  • DNA Damage*
  • DNA Repair*
  • DNA-Binding Proteins*
  • Diffusion
  • Escherichia coli Proteins*
  • Fungal Proteins / physiology*
  • Humans
  • Hydrolysis
  • Magnesium / physiology
  • Models, Genetic
  • MutL Proteins
  • MutS DNA Mismatch-Binding Protein
  • MutS Homolog 2 Protein
  • Protein Conformation
  • Proto-Oncogene Proteins / physiology*
  • Saccharomyces cerevisiae Proteins*


  • Bacterial Proteins
  • DNA-Binding Proteins
  • Escherichia coli Proteins
  • Fungal Proteins
  • MSH6 protein, S cerevisiae
  • MutL protein, E coli
  • Proto-Oncogene Proteins
  • Saccharomyces cerevisiae Proteins
  • Adenosine Triphosphate
  • Adenosine Triphosphatases
  • MSH2 protein, human
  • MutL Proteins
  • MutS DNA Mismatch-Binding Protein
  • MutS Homolog 2 Protein
  • MutS protein, E coli
  • Magnesium