The catalytic subunit of DNA-dependent protein kinase is required for cellular resistance to oxidative stress independent of DNA double-strand break repair.
The catalytic subunit of DNA-dependent protein kinase is required for cellular resistance to oxidative stress independent of DNA double-strand break repair.
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DOI：
10.1016/j.freeradbiomed.2014.08.019
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发表时间：
2014-11
影响因子：
7.4
通讯作者：
Chen, Benjamin P. C.
中科院分区：
文献类型：
--
作者：
Li, Mengxia;Lin, Yu-Fen;Palchik, Guillermo A.;Matsunaga, Shinji;Wang, Dong;Chen, Benjamin P. C.
DNA依赖性蛋白激酶催化亚基（DNA- pkcs）和共济失调毛细血管扩张突变（ATM）是参与DNA双链断裂（DSB）修复的两个主要激酶，并且是细胞抵抗电离辐射所必需的。虽然ATM是DSB信号传导的关键上游激酶，但DNA-PKcs主要通过非同源末端连接（NHEJ）机制参与DSB修复。除了修复DSB外，ATM还参与氧化应激反应，并可在过氧化氢（H2O2）处理下直接在体外激活。然而，DNA-PKcs在细胞氧化应激反应中的作用尚不清楚。我们假设DNA- pkcs可能参与了氧化应激对ATM激活的调节，并且这种调节作用独立于其在DNA双链断裂修复中的作用。我们的研究结果表明，H2O2诱导DNA-PKcs缺陷细胞的ATM信号过度激活，而不是连接酶4缺陷细胞，这表明DNA-PKcs具有nhej独立的作用。此外，DNA-PKcs缺乏导致活性氧（ROS）的产生升高，并降低细胞对H2O2的存活率。我们的研究结果首次揭示了DNA-PKcs在细胞氧化应激反应中起非典型作用，而非独立于其在NHEJ中的作用。此外，DNA-PKcs是氧化应激反应的关键调节因子，有助于维持氧化还原稳态。我们的研究结果表明，DNA-PKcs是细胞抵抗氧化应激和抑制ROS积累所必需的，独立于其在DSB修复中的功能。
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and Ataxia telangiectasia mutated (ATM) are the two major kinases involved in DNA double-strand break (DSB) repair, and are required for cellular resistance to ionizing radiation. While ATM is the key upstream kinase for DSB signaling, DNA-PKcs is primarily involved in DSB repair through the non-homologous end-joining (NHEJ) mechanism. In addition to DSB repair, ATM has been shown to be involved in oxidative stress response and could be activated directly in vitro upon hydrogen peroxide (H2O2) treatment. However, the role of DNA-PKcs in cellular response to oxidative stress is not clear. We hypothesize that DNA-PKcs may participate in the regulation of ATM activation in response to oxidative stress, and that this regulatory role is independent of its role in DNA double strand break repair. Our findings reveal that H2O2 induces hyperactivation of ATM signaling in DNA-PKcs deficient, but not Ligase 4 deficient cells, suggesting an NHEJ-independent role for DNA-PKcs. Furthermore, DNA-PKcs deficiency leads to the elevation of reactive oxygen species (ROS) production, and to a decrease in cellular survival against H2O2. For the first time, our results reveal that DNA-PKcs plays a non-canonical role in the cellular response to oxidative stress, which is independent from its role in NHEJ. In addition, DNA-PKcs is a critical regulator of the oxidative stress response and contributes to the maintenance of redox homeostasis. Our findings reveal that DNA-PKcs is required for cellular resistance to oxidative stress and suppression of ROS build-up independently to its function in DSB repair.
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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：
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影响因子：
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作者：
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Nussenzweig, Michel
影响因子：
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通讯作者：
Bedford, JS
影响因子：
64.8
作者：
FULOP, GM;PHILLIPS, RA
通讯作者：
PHILLIPS, RA
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作者：
Lee, JH;Paull, TT
通讯作者：
Paull, TT