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

Julian E. Sale (), Daniella M. Calandrini, Minoru Takata, Shunichi Takeda and Michael S. Neuberger
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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

Nature, 2001, vol. 412, issue 6850, 921-926

Abstract: 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.

Date: 2001
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DOI: 10.1038/35091100

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