Mechanisms of ATR-mediated checkpoint signalling.

Cell cycle checkpoints maintain genomic integrity by delaying cell division in the presence of DNA damage or replication problems. A crucial player in this process is the ATR kinase. The rapid localisation of ATR to sites of genotoxic stress and the central role of this kinase in the checkpoint response lead to the suggestion that ATR functions as a sensor of DNA lesions. After activation, ATR phosphorylates and activates the effector kinase Chk1, thereby causing an inhibition in cell cycle progression. However, this would not be possible without the existence of many other proteins operating in this pathway. Here we review current progress in our understanding of the regulatory factors involved in the ATR-mediated checkpoint response, as well as resumption of cell cycle progression upon repair of the damage, thereby focussing on the mechanisms in mammalian cells.