Ablation of XRCC2/3 transforms immunoglobulin V gene conversion into somatic hypermutation
Ablation of XRCC2/3 transforms immunoglobulin V gene conversion into somatic hypermutation
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DOI：
10.1038/35091100
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发表时间：
2001-08-30
期刊：
影响因子：
64.8
通讯作者：
Neuberger, MS
中科院分区：
文献类型：
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作者：
Sale, JE;Calandrini, DM;Neuberger, MS
基因重排后，免疫球蛋白V基因通过体细胞超突变或基因转换进一步多样化（1）。超突变（在人和小鼠中）通过个体非模板化核苷酸取代的固定而发生。基因转换（鸡）是由一组上游V假基因模板。在这里，我们表明，如果RAD 51旁系同源物（2）XRCC 2，XRCC 3或RAD 51 B被消除，鸡DT 40 B细胞淋巴瘤系（3）中免疫球蛋白V基因的多样化模式表现出从基因转换到体细胞高突变的明显转变。非模板化的单核苷酸取代以高频率特异性地掺入V结构域中，主要在G/C处并且具有显著的热点偏好。这些突变体DT 40细胞系提供了一个易于处理的模型，免疫球蛋白超突变的遗传解剖和结果支持的想法，基因转换和体细胞超突变构成不同的途径，用于处理一个共同的病变，在免疫球蛋白V基因。通过消融RAD 51旁系同源物实现的体细胞超突变的显著诱导可能是修改这种起始病变的重组介导的修复的结果。
After gene rearrangement, immunoglobulin V genes are further diversified by either somatic hypermutation or gene conversion(1). 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(2) XRCC2, XRCC3 or RAD51B are ablated the pattern of diversification of the immunoglobulin V gene in the chicken DT40 B-cell lymphoma line(3) 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.