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

Author

Listed:
  • Julian E. Sale

    (Medical Research Council Laboratory of Molecular Biology)

  • Daniella M. Calandrini

    (Medical Research Council Laboratory of Molecular Biology)

  • Minoru Takata

    (Immunology and Molecular Genetics, Kawasaki Medical School)

  • Shunichi Takeda

    (CREST Research Project, Radiation Genetics, Faculty of Medicine, Kyoto University)

  • Michael S. Neuberger

    (Medical Research Council Laboratory of Molecular Biology)

Abstract

After gene rearrangement, immunoglobulin V genes are further diversified by either somatic hypermutation or gene conversion1. 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 paralogues2 XRCC2, XRCC3 or RAD51B are ablated the pattern of diversification of the immunoglobulin V gene in the chicken DT40 B-cell lymphoma line3 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.

Suggested Citation

  • Julian E. Sale & Daniella M. Calandrini & Minoru Takata & Shunichi Takeda & Michael S. Neuberger, 2001. "Ablation of XRCC2/3 transforms immunoglobulin V gene conversion into somatic hypermutation," Nature, Nature, vol. 412(6850), pages 921-926, August.
    • Handle: RePEc:nat:nature:v:412:y:2001:i:6850:d:10.1038_35091100
    DOI: 10.1038/35091100
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