Mismatch recognition and uracil excision provide complementary paths to both Ig switching and the A/T-focused phase of somatic mutation

Mol Cell. 2004 Oct 22;16(2):163-71. doi: 10.1016/j.molcel.2004.10.011.


AID-mediated deamination of dC residues within the immunoglobulin locus generates dU:dG lesions whose resolution leads to class-switch recombination and somatic hypermutation. The dU:dG pair is a mismatch and comprises a base foreign to DNA and is, thus, recognized by proteins from both base excision (uracil-DNA glycosylase, UNG) and mismatch recognition (MSH2/MSH6) pathways. Strikingly, while antibody diversification is perturbed by single deficiency in either UNG or MSH2, combined UNG/MSH2 deficiency leads to a total ablation both of switch recombination and of IgV hypermutation at dA:dT pairs. The initiating dU:dG lesions appear not to be recognized and are simply replicated over. The results indicate that the major pathway for switch recombination occurs through uracil excision with mismatch recognition of dU:dG providing a backup; the second phase of hypermutation (essentially introducing mutations solely at dA:dT pairs) is triggered by mismatch recognition of the dU:dG lesion with uracil excision providing a backup.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism
  • DNA Glycosylases / genetics
  • DNA Glycosylases / metabolism
  • DNA Repair / physiology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Immunoglobulin Class Switching / genetics*
  • Immunoglobulin Variable Region / genetics
  • Immunoglobulins / genetics*
  • Mice
  • MutS Homolog 2 Protein
  • Mutation*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Uracil / metabolism*
  • Uracil-DNA Glycosidase


  • DNA-Binding Proteins
  • Immunoglobulin Variable Region
  • Immunoglobulins
  • Proto-Oncogene Proteins
  • Uracil
  • DNA Glycosylases
  • Uracil-DNA Glycosidase
  • Msh2 protein, mouse
  • MutS Homolog 2 Protein