The activation mechanisms of master kinases in the DNA damage response

Abstract

DNA damage can be introduced by intrinsic or extrinsic stimuli and threaten the transmission of genetic information and ultimately, survival. Eukaryotes have evolved a sophisticated mechanism, DNA damage response (DDR), to counteract this threat posed by DNA damage. The DDR requires a series of proteins involved in multiple DNA repair pathways, of which ATM, ATR and DNA–PK serve as the three most critical kinases. The signaling mechanisms underlying these pathways have been extensively studied and these three master kinases structures determined by cryo-electron microscopy (cryo-EM) have led to tremendous progress in understanding the molecular mechanism of the DDR. In this review, we discuss the recent advances made in understanding the structures of ATM, ATR, and DNA–PK. We highlight the implications of these structures in terms of their function and regulation, and speculate on the critical role of PIKK regulatory domain (PRD) in their activation.

Funding

31830107(31830107); 31821002(31821002)