Essential role for DNA-PKcs in DNA double-strand break repair and apoptosis in ATM-deficient lymphocytes.
Essential role for DNA-PKcs in DNA double-strand break repair and apoptosis in ATM-deficient lymphocytes.
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DOI：
10.1016/j.molcel.2009.04.025
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发表时间：
2009-05-15
期刊：
影响因子：
16
通讯作者：
Nussenzweig, Michel
中科院分区：
文献类型：
--
作者：
Callen, Elsa;Jankovic, Mila;Wong, Nancy;Zha, Shan;Chen, Hua-Tang;Difilippantonio, Simone;Di Virgilio, Michela;Heidkamp, Gordon;Alt, Frederick W.;Nussenzweig, Andre;Nussenzweig, Michel
DNA双链断裂(DSB)修复蛋白DNA-PKcs和信号转导分子ATM在体外都被DNA断裂激活并磷酸化类似的底物，但在体内似乎具有不同的功能。在这里，我们展示了ATM和DNA-PKcs在淋巴细胞中的重叠功能。在免疫球蛋白类开关重组的细胞中，两种激酶活性的消融导致开关的复合缺陷，以及由于DSB的异常处理而导致的染色体断裂、DNA插入和易位的协同增加。这些异常是由于DNA修复、类别转换和细胞死亡所需的关键蛋白的磷酸化缺乏所致。值得注意的是，这两种激酶都是B和T细胞中正常水平的P53磷酸化和P53依赖的细胞凋亡所必需的。我们的实验揭示了一条DNA-PKcs依赖的途径，在没有ATM的情况下调节DNA修复和P53的激活。
The DNA double strand break (DSB) repair protein DNA-PKcs and the signal transducer ATM are both activated by DNA breaks and phosphorylate similar substrates in vitro, yet appear to have distinct functions in vivo. Here we show that ATM and DNA-PKcs have overlapping functions in lymphocytes. Ablation of both kinase activities in cells undergoing immunoglobulin class switch recombination leads to a compound defect in switching, and a synergistic increase in chromosomal fragmentation, DNA insertions and translocations due to aberrant processing of DSBs. These abnormalities are attributed to a compound deficiency in phosphorylation of key proteins required for DNA repair, class switching and cell death. Notably, both kinases are required for normal levels of p53 phosphorylation in B and T cells and p53 dependent apoptosis. Our experiments reveal a DNA-PKcs-dependent pathway that regulates DNA repair and activation of p53 in the absence of ATM.
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影响因子：
4.8
作者：
Chen, Benjamin P. C.;Uematsu, Naoya;Chen, David J.
通讯作者：
Chen, David J.
影响因子：
56.9
作者：
Celeste, A;Petersen, S;Nussenzweig, A
通讯作者：
Nussenzweig, A
DOI：
10.1084/jem.20001871
发表时间：
2002-12-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bosma GC;Kim J;Urich T;Fath DM;Cotticelli MG;Ruetsch NR;Radic MZ;Bosma MJ
通讯作者：
Bosma MJ
影响因子：
5.8
作者：
Cowell, IG;Durkacz, BW;Tilby, MJ
通讯作者：
Tilby, MJ
影响因子：
15.3
作者：
Cuadrado, M;Martinez-Pastor, B;Fernandez-Capetillo, O
通讯作者：
Fernandez-Capetillo, O