Mutagenesis dependent upon the combination of activation-induced deaminase expression and a double-strand break
Mutagenesis dependent upon the combination of activation-induced deaminase expression and a double-strand break
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DOI：
10.1016/j.molimm.2010.08.013
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发表时间：
2010-11-01
影响因子：
3.6
通讯作者：
Wilson, Samuel H.
中科院分区：
文献类型：
--
作者：
Poltoratsky, Vladimir;Heacock, Michelle;Wilson, Samuel H.
我们使用酵母模型系统探索了与免疫球蛋白基因体细胞超突变 (SHM) 潜在相关的 DNA 代谢事件 双链断裂 (DSB) 形成已被讨论为免疫球蛋白基因成熟过程中 SHM 过程的一个可能组成部分 然而，将 DSB 形成与诱变联系起来的可能机制尚未得到充分理解 在本研究中，将报告基因诱变与远端位点双链断裂之间的联系作为激活诱导脱氨酶 (AID) 的函数进行了检查发现 DSB 的诱导与位于断裂位点诱变上游 7 kb 的基因组标记基因中的诱变相关，AID 表达和 DSB 诱导的组合最强。这种 DSB 和 AID 介导的诱变的突变谱是一条链中尿嘧啶复制旁路的特征，并且依赖于 DNA 聚合酶 δ (Pol delta) 的表达。酵母模型系统中的这些结果表明，DSB 诱导和 AID 表达的组合可能与观察到的诱变相关。在 SHM 中讨论了这些发现对人类 B 细胞免疫球蛋白基因的 SHM 的影响 由 Elsevier Ltd 出版
We explored DNA metabolic events potentially relevant to somatic hypermutation (SHM) of immunoglobulin genes using a yeast model system Double-strand break (DSB) formation has been discussed as a possible component of the SHM process during immunoglobulin gene maturation Yet possible mechanisms linking DSB formation with mutagenesis have not been well understood In the present study a linkage between mutagenesis in a reporter gene and a double-strand break at a distal site was examined as a function of activation-induced deaminase (AID) expression Induction of the DSB was found to be associated with mutagenesis in a genomic marker gene located 7 kb upstream of the break site mutagenesis was strongest with the combination of AID expression and DSB induction The mutation spectrum of this DSB and AID-mediated mutagenesis was characteristic of replicative bypass of uracil in one strand and was dependent on expression of DNA polymerase delta (Pol delta) These results in a yeast model system illustrate that the combination of DSB induction and AID expression could be associated with mutagenesis observed in SHM Implications of these findings for SHM of immunoglobulin genes in human B cells are discussed Published by Elsevier Ltd