Ablation of XRCC2/3 transforms immunoglobulin V gene conversion into somatic hypermutation

Nature. 2001 Aug 30;412(6850):921-6. doi: 10.1038/35091100.

Abstract

After gene rearrangement, immunoglobulin V genes are further diversified by either somatic hypermutation or gene conversion. Hypermutation (in man and mouse) occurs by the fixation of individual, non-templated nucleotide substitutions. Gene conversion (in chicken) is templated by a set of upstream V pseudogenes. Here we show that if the RAD51 paralogues XRCC2, XRCC3 or RAD51B are ablated the pattern of diversification of the immunoglobulin V gene in the chicken DT40 B-cell lymphoma line exhibits a marked shift from one of gene conversion to one of somatic hypermutation. Non-templated, single-nucleotide substitutions are incorporated at high frequency specifically into the V domain, largely at G/C and with a marked hotspot preference. These mutant DT40 cell lines provide a tractable model for the genetic dissection of immunoglobulin hypermutation and the results support the idea that gene conversion and somatic hypermutation constitute distinct pathways for processing a common lesion in the immunoglobulin V gene. The marked induction of somatic hypermutation that is achieved by ablating the RAD51 paralogues is probably a consequence of modifying the recombination-mediated repair of such initiating lesions.

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • Base Sequence
  • Cell Line
  • Chickens
  • Clone Cells
  • DNA
  • DNA Damage
  • DNA Repair
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Gene Conversion
  • Immunoglobulin Variable Region / genetics*
  • Molecular Sequence Data
  • Mutation
  • Tumor Cells, Cultured

Substances

  • DNA-Binding Proteins
  • Immunoglobulin Variable Region
  • X-ray repair cross complementing protein 3
  • Xrcc2 protein, mouse
  • DNA