A target selection of somatic hypermutations is regulated similarly between T and B cells upon activation-induced cytidine deaminase expression
A target selection of somatic hypermutations is regulated similarly between T and B cells upon activation-induced cytidine deaminase expression
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DOI：
10.1073/pnas.0500830102
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发表时间：
2005-03-22
影响因子：
11.1
通讯作者：
Honjo, T
中科院分区：
文献类型：
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作者：
Kotani, A;Okazaki, I;Honjo, T
激活诱导的胞苷脱氨酶（AID）是体细胞超突变（SHIM）和类别转换重组所必需的。AID在非B细胞中的过表达可以诱导插入基因组中的各种基因座中的人工构建体中的SHM。因此，提出了AID过表达在多种基因中引入突变而几乎没有特异性。我们以前发现，艾滋病转基因小鼠发展的T细胞淋巴瘤中的T细胞受体和c-myc的可变区13基因突变的频繁SHM在活化的B细胞。为了了解SHM在表达AIDS的T淋巴瘤中的靶特异性，我们对T淋巴瘤中转录活跃的6个癌基因（c-myc、pim 1、p53、atm、tgfbr-2和k-ras）和2个基因（cd 4和cd 5）进行了测序。SHIM仅在c-myc、pim 1、cd 4和cd 5中发现，它们在增强子/启动子中共享E47结合基序。其余在B细胞中没有突变的基因在艾滋病诱导的T淋巴瘤中也没有突变，尽管它们在T和B细胞中转录。比较SHM的几个特征，包括靶点的选择和突变分布，表明SHIM的调节机制在T和B细胞之间是相似的。CD 4和CD 5基因的SHIM碱基特异性偏向AT，表明AID过表达产生的突变的靶碱基的偏好不总是GC碱基，而是在靶基因之间可变。
Activation-induced cytidine deaminase (AID) is essential for somatic hypermutations (SHIM) and class switch recombination. Overexpression of AID in non-B cells can induce SHM in artificial constructs inserted in various loci in the genome. AID overexpression was thus proposed to introduce mutations in a wide variety of genes with little specificity. We previously showed that AID transgenic mice developed T cell lymphomas in which the variable region 13 genes of the T cell receptor and c-myc were mutated as frequently as SHM in activated B cells. To understand the target specificity of SHM in AID-expressing T lymphomas, we sequenced six oncogenes (c-myc, pim1, p53, atm, tgfbr-2, and k-ras) and two genes (cd4 and cd5) that are actively transcribed in T lymphomas. SHIM was found only in c-myc, pim1, cd4, and cd5, which share the E47 binding motif in the enhancer/promoter. The rest that are not mutated in B cells were not mutated in AID-induced T lymphomas either, although they are transcribed in T and B cells. Comparison of several features of SHM, including selection of targets and mutation distribution, suggests that the regulatory mechanism of SHIM is similar between T and B cells. SHIM base specificities in the CD4 and CD5 genes were biased to AT, indicating that the preference of target bases of the mutations generated by overexpression of AID is not always GC bases but variable between target genes.