NBS1 regulates a novel apoptotic pathway through Bax activation
NBS1 regulates a novel apoptotic pathway through Bax activation
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DOI：
10.1016/j.dnarep.2008.06.013
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发表时间：
2008-10-01
期刊：
影响因子：
3.8
通讯作者：
Tauchi, Hiroshi
中科院分区：
文献类型：
--
作者：
Iijima, Kenta;Muranaka, Chizuko;Tauchi, Hiroshi
DNA损伤诱导的细胞凋亡，沿着精确的DNA损伤修复，是一种关键的细胞功能，这两种功能对于癌症预防都是必需的。已知NBS 1蛋白是DNA损伤修复的关键调节因子。它通过与Rad 50/Mre 11形成复合物并激活ATM来发挥作用。我们在这里表明，NBS 1调节一种新的p53非依赖性细胞凋亡途径，以响应DNA损伤。DNA损伤诱导的细胞凋亡显着减少NBS 1缺陷的细胞，无论他们的p53状态。使用一系列表达突变型NBS 1蛋白的细胞系的实验表明，NBS 1能够调节Bax和Caspase-3的激活，而无需FHA、Mre 11结合或ATM相互作用结构域，而NBS 1的磷酸化位点对于Bax激活是必需的。凋亡相关转录因子如E2 F1及其下游促凋亡因子的表达与这种凋亡诱导无关。有趣的是，NBS 1通过破坏Ku 70-Bax复合物来调节一种新的Bax激活途径，该复合物是激活线粒体凋亡途径所必需的。Ku 70-Bax复合物的这种解离可以通过Ku 70的乙酰化介导，并且NBS 1可以通过与Ku 70的蛋白质-蛋白质相互作用在该过程中发挥作用。因此，NBS 1是参与预防癌发生的关键蛋白，不仅通过同源重组（HR）精确修复受损DNA，而且通过其在消除不适当修复细胞中的作用。(c)2008 Elsevier B. V.保留所有权利。
DNA damage induced apoptosis, along with precise DNA damage repair, is a critical cellular function, and both of these functions are necessary for cancer prevention. The NBS1 protein is known to be a key regulator of DNA damage repair. It acts by forming a complex with Rad50/Mre11 and by activating ATM. We show here that NBS1 regulates a novel p53 independent apoptotic pathway in response to DNA damage. DNA damage induced apoptosis was significantly reduced in NBS1 deficient cells regardless of their p53 status. Experiments using a series of cell lines expressing mutant NBS1 proteins revealed that NBS1 is able to regulate the activation of Bax and Caspase-3 without the FHA, Mre11-binding, or the ATM-interacting domains, whereas the phosphorylation sites of NBS1 were essential for Bax activation. Expression of apoptosis-related transcription factors such as E2F1 and their downstream pro-apoptotic factors were not related to this apoptosis induction. Interestingly, NBS1 regulates a novel Bax activation pathway by disrupting the Ku70-Bax complex which is required for activation of the mitochondrial apoptotic pathway. This dissociation of the Ku70-Bax complex can be mediated by acetylation of Ku70, and NBS1 can function in this process through a protein-protein interaction with Ku70. Thus, NBS1 is a key protein involved in the prevention of carcinogenesis, not only through the precise repair of damaged DNA by homologous recombination (HR) but also by its role in the elimination of inappropriately repaired cells. (c) 2008 Elsevier B.V. All rights reserved.