Skaggs Institute for Chemical Biology, Department of Molecular Biology, La Jolla, CA 92037, USA.
Sci Signal. 2011 Apr 5;4(167):pe18. doi: 10.1126/scisignal.2001961.
Ataxia-telangiectasia (A-T) is a rare, neurodegenerative, inherited disease arising from mutations in the kinase A-T mutated (ATM), which promotes cell cycle checkpoints and DNA double-strand break repair. Puzzlingly, these ATM activities fail to fully explain A-T neuropathologies, which instead have links to stress induced by reactive oxygen species (ROS). However, a landmark discovery reveals an unexpected intersection of ROS and kinase signaling: ATM can be directly activated by oxidation to form a disulfide-linked dimer in a mechanism distinct from DNA damage activation. When combined with notable structural-based insights into the ATM homolog DNA-PK (DNA-protein kinase) and mTOR (mammalian target of rapamycin), these results suggest conformation and assembly mechanisms to signal oxidative stress through an ATM nodal point. These findings fundamentally affect our understanding of ROS and ATM signaling and of the A-T phenotype, with implications for altering signaling in cancer cells to increase sensitivities to current therapeutic interventions.
共济失调毛细血管扩张症（A-T）是一种罕见的神经退行性遗传性疾病，由激酶 A-T 突变（ATM）的突变引起，该激酶可促进细胞周期检查点和 DNA 双链断裂修复。令人费解的是，这些 ATM 活性未能完全解释 A-T 的神经病理学，而这些病理学与活性氧（ROS）诱导的应激有关。然而，一项具有里程碑意义的发现揭示了 ROS 和激酶信号之间出人意料的交叉：ATM 可以通过氧化直接激活，形成一种不同于 DNA 损伤激活的二硫键连接的二聚体。当与 ATM 同源物 DNA-PK（DNA 蛋白激酶）和 mTOR（雷帕霉素靶蛋白）的显著基于结构的见解相结合时，这些结果表明通过 ATM 节点通过氧化应激传递信号的构象和组装机制。这些发现从根本上影响了我们对 ROS 和 ATM 信号以及 A-T 表型的理解，这对改变癌细胞中的信号以提高对当前治疗干预的敏感性具有重要意义。
