New Insights into Checkpoint Kinase 1 in the DNA Damage Response Signaling Network

Chk1 in the DDR signaling network. DNA damage (e.g., DSBs, SSBs, and stalled replication forks) generates ssDNA that initiates ATR-mediated Chk1 activation. In this context, the ATR/ATPIP complex is recruited to ssDNA lesions via binding of ATRIP with RPA that recognizes and coats ssDNA. In conjunction with recruited/activated sensors and mediators, ATR phosphorylates Chk1 at two canonical sites (Ser345 and S317), directly leading to its activation without the homodimerization and intramolecular trans-autophosphorylation that is required for Chk2 activation. Activated Chk1 then phosphorylates diverse downstream effectors, which in turn are involved in cell cycle checkpoints (i.e., intra-S-phase, G2/M-phase, and G1/S-phase checkpoints), the DNA replication checkpoint, and the mitotic spindle checkpoint, as well as DNA repair, apoptosis, and transcription. Consequently, Chk1 is a kinase central for the DDR signaling network, thereby representing a particularly attractive target in anticancer therapeutics.