Molecular mechanisms of antibody somatic hypermutation

Annu Rev Biochem. 2007;76:1-22. doi: 10.1146/annurev.biochem.76.061705.090740.

Abstract

Functional antibody genes are assembled by V-D-J joining and then diversified by somatic hypermutation. This hypermutation results from stepwise incorporation of single nucleotide substitutions into the V gene, underpinning much of antibody diversity and affinity maturation. Hypermutation is triggered by activation-induced deaminase (AID), an enzyme which catalyzes targeted deamination of deoxycytidine residues in DNA. The pathways used for processing the AID-generated U:G lesions determine the variety of base substitutions observed during somatic hypermutation. Thus, DNA replication across the uracil yields transition mutations at C:G pairs, whereas uracil excision by UNG uracil-DNA glycosylase creates abasic sites that can also yield transversions. Recognition of the U:G mismatch by MSH2/MSH6 triggers a mutagenic patch repair in which polymerase eta plays a major role and leads to mutations at A:T pairs. AID-triggered DNA deamination also underpins immunoglobulin variable (IgV) gene conversion, isotype class switching, and some oncogenic translocations in B cell tumors.

Publication types

  • Review

MeSH terms

  • Animals
  • Antibodies
  • Cytidine Deaminase / genetics
  • Cytidine Deaminase / metabolism
  • DNA / genetics
  • DNA / metabolism
  • DNA Damage
  • DNA Repair
  • DNA-Binding Proteins / metabolism
  • Genes, Immunoglobulin
  • Humans
  • Immunoglobulin Class Switching
  • MutS Homolog 2 Protein / metabolism
  • Mutation
  • Recombination, Genetic*
  • Somatic Hypermutation, Immunoglobulin*
  • Transcription, Genetic
  • Uracil / metabolism

Substances

  • Antibodies
  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • Uracil
  • DNA
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase
  • MutS Homolog 2 Protein