Two levels of protection for the B cell genome during somatic hypermutation
Two levels of protection for the B cell genome during somatic hypermutation
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DOI：
10.1038/nature06547
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发表时间：
2008-02-14
期刊：
影响因子：
64.8
通讯作者：
Schatz, David G.
中科院分区：
文献类型：
--
作者：
Liu, Man;Duke, Jamie L.;Schatz, David G.
体细胞超突变在免疫应答期间将点突变引入到生殖中心B细胞中的免疫球蛋白基因中。该反应由活化诱导的脱氨酶（AID）的胞嘧啶脱氨基作用引发，并通过错配和碱基切除修复因子对所得尿嘧啶的易错加工完成（1）。体细胞超突变代表了对基因组完整性的威胁（2），并且不知道如何保护B细胞基因组免受体细胞超突变的诱变效应，也不知道这些保护机制失败的频率。在这里，我们通过对鼠B细胞基因的广泛测序表明，基因组受到两种不同机制的保护：AID的选择性靶向和AID产生的尿嘧啶的基因特异性高保真修复。许多与B细胞肿瘤发生相关的基因，包括Myc、Pim 1、Pax 5、Ocab（也称为Pou2af 1）、H2afx、Rhoh和Ebf 1，被AID脱氨基，但通过错配和碱基切除修复的联合作用而逃避大多数突变的获得。然而，大约25%的表达基因的分析没有得到充分的保护，无论是机制和积累的突变，在生发中心B细胞。我们的研究结果表明，艾滋病广泛作用于基因组，最终的突变分布由高保真和易错DNA修复之间的平衡决定。
Somatic hypermutation introduces point mutations into immunoglobulin genes in germinal centre B cells during an immune response. The reaction is initiated by cytosine deamination by the activation- induced deaminase ( AID) and completed by error- prone processing of the resulting uracils by mismatch and base excision repair factors(1). Somatic hypermutation represents a threat to genome integrity(2) and it is not known how the B cell genome is protected from the mutagenic effects of somatic hypermutation nor how often these protective mechanisms fail. Here we show, by extensive sequencing of murine B cell genes, that the genome is protected by two distinct mechanisms: selective targeting of AID and gene- specific, high- fidelity repair of AID- generated uracils. Numerous genes linked to B cell tumorigenesis, including Myc, Pim1, Pax5, Ocab ( also called Pou2af1), H2afx, Rhoh and Ebf1, are deaminated by AID but escape acquisition of most mutations through the combined action of mismatch and base excision repair. However, approximately 25% of expressed genes analysed were not fully protected by either mechanism and accumulated mutations in germinal centre B cells. Our results demonstrate that AID acts broadly on the genome, with the ultimate distribution of mutations determined by a balance between high- fidelity and error- prone DNA repair.