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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >DNA polymerase θ contributes to the generation of C/G mutations during somatic hypermutation of Ig genes
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DNA polymerase θ contributes to the generation of C/G mutations during somatic hypermutation of Ig genes

机译：DNA聚合酶θ有助于Ig基因的体细胞超突变过程中C / G突变的产生

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摘要

Somatic hypermutation of Ig variable region genes is initiated by activation-induced cytidine deaminase; however, the activity of multiple DNA polymerases is required to ultimately introduce mutations. DNA polymerase η (Pol η) has been implicated in mutations at A/T, but polymerases involved in C/G mutations have not been identified. We have generated mutant mice expressing DNA polymerase (Polθ) specifically devoid of polymerase activity. Compared with WT mice, Polq-inactive (Polq, the gene encoding Polθ) mice exhibited a reduced level of serum IgM and lgG1. The mutant mice mounted relatively normal primary and secondary immune responses to a T-dependent antigen, but the production of high-affinity specific antibodies was partially impaired. Analysis of the J_H4 intronic sequences revealed a slight reduction in the overall mutation frequency in Polq-inactive mice. Remarkably, although mutations at A/T were unaffected, mutations at C/G were significantly decreased, indicating an important, albeit not exclusive, role for Polθ activity. The reduction of C/G mutations was particularly focused on the intrinsic somatic hypermutation hotspots and both transitions and transversions were similarly reduced. These findings, together with the recent observation that Polθ efficiently catalyzes the bypass of abasic sites, lead us to propose that Polθ introduces mutations at C/G by replicating over abasic sites generated via uracil-DNA glycosylase.
机译：Ig可变区基因的体细胞超突变是由激活诱导的胞苷脱氨酶引发的。然而，多种DNA聚合酶的活性是最终引入突变所必需的。 DNA聚合酶η（Polη）与A / T突变有关，但尚未鉴定出与C / G突变有关的聚合酶。我们已经生成了表达DNA聚合酶（Polθ）特别是缺乏聚合酶活性的突变小鼠。与野生型小鼠相比，Polq失活（Polq，编码Polθ的基因）小鼠的血清IgM和IgG1水平降低。突变小鼠对T依赖性抗原具有相对正常的一级和二级免疫反应，但部分削弱了高亲和力特异性抗体的产生。对J_H4内含子序列的分析显示，在无Polq活性的小鼠中总体突变频率略有降低。值得注意的是，尽管A / T处的突变不受影响，但C / G处的突变却显着减少，这表明尽管不是排他性的，但对Polθ活性却起着重要作用。 C / G突变的减少特别着重于内在的体细胞超突变热点，并且转变和颠换都同样减少。这些发现以及最近关于Polθ有效催化无碱基位点旁路的观察结果，导致我们提出Polθ通过在尿嘧啶DNA糖基化酶产生的无碱基位点上复制来在C / G处引入突变。

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