Department of Immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2479-84. doi: 10.1073/pnas.1120791109. Epub 2012 Jan 30.
Activation-induced cytidine deaminase (AID) is required for both somatic hypermutation and class-switch recombination in activated B cells. AID is also known to target nonimmunoglobulin genes and introduce mutations or chromosomal translocations, eventually causing tumors. To identify as-yet-unknown AID targets, we screened early AID-induced DNA breaks by using two independent genome-wide approaches. Along with known AID targets, this screen identified a set of unique genes (SNHG3, MALAT1, BCL7A, and CUX1) and confirmed that these loci accumulated mutations as frequently as Ig locus after AID activation. Moreover, these genes share three important characteristics with the Ig gene: translocations in tumors, repetitive sequences, and the epigenetic modification of chromatin by H3K4 trimethylation in the vicinity of cleavage sites.
激活诱导胞嘧啶脱氨酶(AID)是激活 B 细胞中体细胞超突变和类别转换重组所必需的。AID 也已知靶向非免疫球蛋白基因并引入突变或染色体易位,最终导致肿瘤。为了鉴定迄今为止未知的 AID 靶标,我们使用两种独立的全基因组方法筛选了早期 AID 诱导的 DNA 断裂。除了已知的 AID 靶标外,该筛选还鉴定了一组独特的基因(SNHG3、MALAT1、BCL7A 和 CUX1),并证实这些基因座在 AID 激活后与 Ig 基因一样频繁地积累突变。此外,这些基因与 Ig 基因具有三个重要特征:肿瘤中的易位、重复序列以及邻近切割位点处组蛋白 H3K4 三甲基化的染色质的表观遗传修饰。