Differential roles of ATR and ATM in p53, Chk1, and histone H2AX phosphorylation in response to hyperoxia: ATR-dependent ATM activation
Differential roles of ATR and ATM in p53, Chk1, and histone H2AX phosphorylation in response to hyperoxia: ATR-dependent ATM activation
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DOI：
10.1152/ajplung.00004.2008
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发表时间：
2008-05-01
影响因子：
4.9
通讯作者：
Das, Kumuda C.
中科院分区：
文献类型：
--
作者：
Kulkarni, Amit;Das, Kumuda C.
升高氧气水平（高氧）广泛应用于重症监护病房和呼吸功能不全的情况。此外，高氧还与许多疾病有关，例如支气管肺发育不良或急性呼吸窘迫综合征。尽管已知高氧会导致 DNA 碱基修饰和链断裂，但 DNA 损伤反应尚未得到充分研究。我们研究了高氧对 DNA 损伤信号传导的影响，并表明高氧是一种独特的应激，可激活共济失调毛细血管扩张突变体 (ATM) 和 Rad3 相关蛋白激酶 (ATR) 依赖性 p53 磷酸化（Ser6、-15、-37 和 -392）、组蛋白 H2AX (Ser139) 磷酸化和检查点激酶 1 (Chk1) 磷酸化。此外，我们还发现 p53 (Ser6) 和组蛋白 H2AX (Ser139) 的磷酸化取决于 ATM 和 ATR。我们证明，在高氧条件下，ATR 激活先于 ATM 激活。最后，我们证明 ATR 是高氧条件下 ATM 激活所必需的。综上所述，我们报告 ATR 是高氧条件下激活 ATM 的主要 DNA 损伤信号转导器。
Elevated level of oxygen (hyperoxia) is widely used in critical care units and in respiratory insufficiencies. In addition, hyperoxia has been implicated in many diseases such as bronchopulmonary dysplasia or acute respiratory distress syndrome. Although hyperoxia is known to cause DNA base modifications and strand breaks, the DNA damage response has not been adequately investigated. We have investigated the effect of hyperoxia on DNA damage signaling and show that hyperoxia is a unique stress that activates the ataxia telangiectasia mutant (ATM)and Rad3-related protein kinase (ATR)-dependent p53 phosphorylations (Ser6, -15, -37, and -392), phosphorylation of histone H2AX (Ser139), and phosphorylation of checkpoint kinase 1 (Chk1). In addition, we show that phosphorylation of p53 ( Ser6) and histone H2AX ( Ser139) depend on both ATM and ATR. We demonstrate that ATR activation precedes ATM activation in hyperoxia. Finally, we show that ATR is required for ATM activation in hyperoxia. Taken together, we report that ATR is the major DNA damage signal transducer in hyperoxia that activates ATM.