Involvement of Rad18 in somatic hypermutation
Involvement of Rad18 in somatic hypermutation
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DOI：
10.1073/pnas.0605146103
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发表时间：
2006-08-08
影响因子：
11.1
通讯作者：
Jungnickel, Berit
中科院分区：
文献类型：
--
作者：
Bachl, Juergen;Ertongur, Isin;Jungnickel, Berit
Ig基因的体细胞超突变是由Ig位点的转录偶联胞苷脱氨引起的。由此产生的DNA损伤的易出错处理被认为会引起广泛的突变，但目前仍是一个谜，如何以及为什么会招募易出错而不是无错误的修复途径。在DNA复制过程中，容易出错的翻译聚合酶的募集可能由Rad6/ rad18介导的增殖细胞核抗原泛素化介导，这是控制真核生物DNA病变旁路保真度的主要开关板。通过在dt40b细胞系中灭活Rad18，我们发现Rad6通路参与了这些细胞的体细胞超突变。我们的研究结果表明，通过Rad6途径靶向募集诱变聚合酶有助于体细胞超突变的复杂过程，并为继发性Ig多样化的诱变阶段更详细的机制研究提供了框架。
Somatic hypermutation of Ig genes is initiated by transcription-coupled cytidine deamination in Ig loci. Error-prone processing of the resultant DNA lesions is thought to cause extensive mutagenesis, but it is presently an enigma how and why error-prone rather than error-free repair pathways are recruited. During DNA replication, recruitment of error-prone translesion polymerases may be mediated by Rad6/Rad18-mediated ubiquitination of proliferating cell nuclear antigen, a major switchboard controlling the fidelity of DNA lesion bypass in eukaryotes. By inactivation of Rad18 in the DT40 B cell line, we show that the Rad6 pathway is involved in somatic hypermutation in these cells. Our findings imply that targeted recruitment of mutagenic polymerases by the Rad6 pathway contributes to the complex process of somatic hypermutation and provide a framework for more detailed mechanistic studies of the mutagenesis phase of secondary Ig diversification.