ATRChk1

ATRChk1 refers to the ATR-Chk1 signaling axis, a major component of the eukaryotic DNA damage response that links detection of replication stress to cell cycle control and DNA repair. In response to replication stress or ultraviolet-induced damage, long regions of single-stranded DNA are coated with RPA, which recruits the ATR-ATRIP complex to chromatin. Activation is enhanced by the activators TopBP1 and ETAA1. ATR then phosphorylates and activates Chk1 at multiple sites, including serine 345 in humans.

Active Chk1 enforces the checkpoint mainly by inhibiting Cdc25 phosphatases. Phosphorylation of Cdc25A prevents CDK2 activation, slowing S-phase progression, while Cdc25C inhibition prevents mitotic entry, enforcing G2/M arrest. Additional Chk1 substrates coordinate fork stability, replication origin firing, and DNA repair, helping to stabilize stalled forks and allow time for lesion repair.

Functionally, the ATRChk1 pathway preserves genome integrity by delaying cell cycle progression until replication stress is resolved. Defects in this axis can lead to genome instability and cancer predisposition, while many tumors become reliant on ATR-Chk1 signaling to cope with high replication stress. Clinically, ATR inhibitors are being explored to sensitize tumors to chemotherapy and radiotherapy, particularly in cancers with p53 defects or high replication-stress phenotypes. The ATR-Chk1 axis is highly conserved across eukaryotes and interacts with other DDR pathways, including ATM and p53, to coordinate comprehensive DNA damage responses.