The DNA damage response (DDR) is orchestrated by three apical signalling kinases: ATM, ATR and DNA-PKcs. Despite their central roles, structural and biochemical understanding has remained limited, mainly due to their large size. Recent advances in cryo-electron microscopy allowed for the structural analysis of these kinases, revealing their overall architecture and providing high resolution structures of their active sites. Combined with novel biochemical insights it is now possible to dissect the elements that are important for activation. In this review we discuss the recent structures of these kinases, the possible mechanisms to regulate their activity, substrate recognition and emerging insights in the elements required for kinase activation.

DNA 损伤反应 (DDR) 由三种顶端信号激酶协调：ATM、ATR 和 DNA-PKcs。尽管它们发挥着核心作用，但结构和生化的理解仍然有限，主要是由于它们的尺寸很大。冷冻电子显微镜的最新进展允许对这些激酶进行结构分析，揭示它们的整体结构并提供其活性位点的高分辨率结构。结合新的生化见解，现在可以剖析对激活很重要的元素。在这篇综述中，我们讨论了这些激酶的最新结构、调节其活性的可能机制、底物识别和对激酶激活所需元素的新见解。