Aberrantly resolved RAG-mediated DNA breaks in Atm-deficient lymphocytes target chromosomal breakpoints in cis
Aberrantly resolved RAG-mediated DNA breaks in Atm-deficient lymphocytes target chromosomal breakpoints in cis
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DOI：
10.1073/pnas.0902545106
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发表时间：
2009-10-27
影响因子：
11.1
通讯作者：
Sleckman, Barry P.
中科院分区：
文献类型：
--
作者：
Mahowald, Grace K.;Baron, Jason M.;Sleckman, Barry P.
典型的染色体易位，抗原受体基因和癌基因并列是许多淋巴系统恶性肿瘤的特征。这些易位通常是由重组酶激活基因(RAG)-1和-2蛋白在淋巴细胞抗原受体位点和癌基因附近的断裂点靶点产生的双链断裂(DSB)的DNA末端连接而形成的。我们对染色体断点目标选择的理解主要来自对这些损伤的分析，这些损伤是根据它们的转化特性选择的。RAG DSB很少在野生型发育中的淋巴细胞中异常分解。然而，在共济失调毛细血管扩张突变(ATM)缺陷淋巴细胞中，RAG断裂经常被异常连接，形成染色体损伤，如易位，使(ATM)缺陷小鼠和人类容易发生淋巴样恶性肿瘤。这里，一种最小化选择偏差的方法被用来分离ATM缺陷淋巴细胞中异常分解的RAG DSB的大量断点靶标。对这一队列的分析表明，通常情况下，异常解析的RAG断裂的断点目标是其他DSB。此外，这些非选择性病变倾向于在顺式染色体中使用断点，形成小的染色体缺失，而不是在反式中使用断点，形成染色体易位。
Canonical chromosomal translocations juxtaposing antigen receptor genes and oncogenes are a hallmark of many lymphoid malignancies. These translocations frequently form through the joining of DNA ends from double-strand breaks (DSBs) generated by the recombinase activating gene (RAG)-1 and -2 proteins at lymphocyte antigen receptor loci and breakpoint targets near oncogenes. Our understanding of chromosomal breakpoint target selection comes primarily from the analyses of these lesions, which are selected based on their transforming properties. RAG DSBs are rarely resolved aberrantly in wild-type developing lymphocytes. However, in ataxia telangiectasia mutated (ATM)-deficient lymphocytes, RAG breaks are frequently joined aberrantly, forming chromosomal lesions such as translocations that predispose (ATM)deficient mice and humans to the development of lymphoid malignancies. Here, an approach that minimizes selection biases is used to isolate a large cohort of breakpoint targets of aberrantly resolved RAG DSBs in Atm-deficient lymphocytes. Analyses of this cohort revealed that frequently, the breakpoint targets for aberrantly resolved RAG breaks are other DSBs. Moreover, these nonselected lesions exhibit a bias for using breakpoints in cis, forming small chromosomal deletions, rather than breakpoints in trans, forming chromosomal translocations.