ATR
ATR (ATM- and Rad3-related) is a serine/threonine kinase activated by replication stress - stalled replication forks and the single-stranded DNA exposed during repair.
Function
ATR is recruited by its partner ATRIP to single-stranded DNA coated with RPA, the structure that appears whenever a replication fork stalls or a resected break is awaiting repair. Activated ATR phosphorylates CHK1, which then enforces the intra-S and G2/M checkpoints, stabilizes stalled forks, suppresses origin firing elsewhere in the genome, and coordinates repair. The ATR-CHK1 arm therefore protects cells through S and G2, the phases in which unreplicated or partially replicated DNA would otherwise be segregated into daughter cells. Topoisomerase poisons, hydroxyurea, UV damage, and oncogene-induced replication stress all signal through ATR.
In cancer
ATR loss is lethal to most cells, but tumors with high baseline replication stress - those driven by oncogenes, or deficient in p53 - depend on ATR for survival more heavily than normal tissue does. ATR inhibitors exploit this dependency, and synthetic-lethal combinations pairing ATR inhibition with ATM loss or chemotherapy are in clinical trials.
Notes
- Human gene symbol: ATR; UniProt Q13535; 2,644 amino acids; PI3K-related kinase (PIKK) family.