Aberrant V(D)J recombination in ataxia telangiectasia mutated-deficient lymphocytes is dependent on nonhomologous DNA end joining.
Aberrant V(D)J recombination in ataxia telangiectasia mutated-deficient lymphocytes is dependent on nonhomologous DNA end joining.
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DOI：
10.4049/jimmunol.181.4.2620
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发表时间：
2008-08-15
期刊：
影响因子：
--
通讯作者：
Sleckman BP
中科院分区：
文献类型：
--
作者：
Bredemeyer AL;Huang CY;Walker LM;Bassing CH;Sleckman BP
在淋巴细胞抗原受体基因组装过程中，通过Rag蛋白的DNA切割产生成对的编码和信号末端，其通常通过DNA双链断裂（DSB）修复的经典非同源末端连接（NHEJ）途径分别连接成编码接头和信号接头。编码和信号末端也可以通过NHEJ或通过NHEJ非依赖性途径（例如Rag介导的转座）异常地彼此连接，产生杂交接头。杂交接头不参与功能性抗原受体基因的形成，并且可以以限制随后的生产性重排的方式改变抗原受体基因座的构型。这些非功能性杂交接头的形成很少发生在野生型淋巴细胞中，表明存在限制信号末端与编码末端的NHEJ依赖性和NHEJ非依赖性连接的机制。与野生型细胞相反，在Atm缺陷的淋巴细胞中，杂交关节形成以高水平发生，这表明Atm的功能限制了这些异常关节的形成。在这里，我们表明，在ATM缺陷细胞中的混合联合形成需要NHEJ蛋白Artemis，DNA-PKcs和Ku 70，表明ATM的功能主要是通过调节NHEJ依赖的，而不是NHEJ独立的，连接的编码端信号端。
During lymphocyte antigen receptor gene assembly, DNA cleavage by the Rag proteins generates pairs of coding and signal ends that are normally joined into coding joints and signal joints, respectively, by the classical non-homologous end-joining (NHEJ) pathway of DNA double strand break (DSB) repair. Coding and signal ends can also be aberrantly joined to each other, generating hybrid joints, through NHEJ or through NHEJ-independent pathways, such as Rag-mediated transposition. Hybrid joints do not participate in the formation of functional antigen receptor genes and can alter the configuration of antigen receptor loci in ways that limit subsequent productive rearrangements. The formation of these non-functional hybrid joints occurs rarely in wild type lymphocytes, demonstrating that mechanisms exist to limit both the NHEJ-dependent and the NHEJ-independent joining of a signal end to a coding end. In contrast to wild type cells, hybrid joint formation occurs at high levels in Atm-deficient lymphocytes, suggesting that Atm functions to limit the formation of these aberrant joints. Here we show that hybrid joint formation in Atm-deficient cells requires the NHEJ proteins Artemis, DNA-PKcs and Ku70, demonstrating that Atm functions primarily by modulating the NHEJ-dependent, and not the NHEJ-independent, joining of coding ends to signal ends.
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影响因子：
64.8
作者：
Agrawal, A;Eastman, QM;Schatz, DG
通讯作者：
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DOI：
10.1073/pnas.95.26.15559
发表时间：
1998-12-22
影响因子：
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