Structural basis of the (in)activity of the apical DNA damage response kinases ATM, ATR and DNA-PKcs.

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.