通过氧化应激的ATM激活
Zhi Guo1, Sergei Kozlov, Martin F Lavin
1Howard Hughes Medical Institute, Department of Molecular Genetics and Microbiology, and Institute for Cellular and Molecular Biology (ICMB), University of Texas at Austin, Austin, TX 78712, USA.
概括
氧化直接激活了阿塔克西亚 - 泰朗基切塔西亚突变 (ATM) 蛋白激酶,独立于DNA损伤. 这一发现揭示了ATM是人类细胞中氧化应激和活性氧物种的关键传感器.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 细胞信号传输 细胞信号传输
背景情况:
- 动脉动脉突变 (ATM) 蛋白激酶是DNA损伤反应的关键调节剂,主要通过Mre11-Rad50-Nbs1 (MRN) 复合体通过DNA双链断裂 (DSB) 激活.
- 缺乏ATM的细胞对包括氧化应激在内的各种细胞攻击具有过敏性,这表明DSB修复之外的作用.
研究的目的:
- 在氧化应激条件下研究ATM的直接激活机制.
- 为了确定ATM是否可以独立于DNA双链断裂和MRN复合体而被激活.
主要方法:
- 生物化学分析检测ATM激活和二元化.
- 在ATM中的关键氨酸残留物的位点定向突变发生.
- 细胞测试用于评估对氧化剂的反应中的ATM激活.
主要成果:
- 氧化直接诱导ATM激活,形成二硫化物交联二聚体,独立于DNADSB和MRN复合体.
- 通过氧化途径对特定的氨酸残留物的突变取消了ATM激活.
- 这种途径解释了在氧化应激条件下观察到的ATM激活.
结论:
- 机器人充当反应性氧物种 (ROS) 的直接传感器.
- 氧化修饰代表了ATM激活的新,直接的途径.
- 这一发现扩大了对ATM在细胞应激反应中的作用的理解.
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