MSH2-MSH6 stimulates DNA polymerase eta, suggesting a role for A:T mutations in antibody genes

J Exp Med. 2005 Feb 21;201(4):637-45. doi: 10.1084/jem.20042066. Epub 2005 Feb 14.


Activation-induced cytidine deaminase deaminates cytosine to uracil (dU) in DNA, which leads to mutations at C:G basepairs in immunoglobulin genes during somatic hypermutation. The mechanism that generates mutations at A:T basepairs, however, remains unclear. It appears to require the MSH2-MSH6 mismatch repair heterodimer and DNA polymerase (pol) eta, as mutations of A:T are decreased in mice and humans lacking these proteins. Here, we demonstrate that these proteins interact physically and functionally. First, we show that MSH2-MSH6 binds to a U:G mismatch but not to other DNA intermediates produced during base excision repair of dUs, including an abasic site and a deoxyribose phosphate group. Second, MSH2 binds to pol eta in solution, and endogenous MSH2 associates with the pol in cell extracts. Third, MSH2-MSH6 stimulates the catalytic activity of pol eta in vitro. These observations suggest that the interaction between MSH2-MSH6 and DNA pol eta stimulates synthesis of mutations at bases located downstream of the initial dU lesion, including A:T pairs.

Publication types

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

MeSH terms

  • Base Pair Mismatch
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • DNA-Directed DNA Polymerase / metabolism*
  • HeLa Cells
  • Humans
  • MutS Homolog 2 Protein
  • Protein Binding
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Somatic Hypermutation, Immunoglobulin*


  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • Proto-Oncogene Proteins
  • DNA-Directed DNA Polymerase
  • MSH2 protein, human
  • MutS Homolog 2 Protein