ATR (ataxia-telangiectasia and Rad3-related) is a serine/threonine protein kinase that functions as a master DNA damage sensor, activating checkpoint signaling in response to genotoxic stresses including ionizing radiation, ultraviolet light, and DNA replication stress 1. The kinase recognizes substrate consensus sequences [ST]-Q and phosphorylates critical checkpoint proteins including CHEK1, p53, BRCA1, and H2AX, collectively inhibiting DNA replication and mitosis while promoting DNA repair and apoptosis 1. ATR mechanistically couples local fork protection with global suppression of origin firing to prevent replication catastrophe by maintaining adequate RPA pools 2. Beyond canonical DDR functions, ATR regulates the G2/M transition, maintains nuclear envelope integrity under DNA damage and mechanical stress, and promotes clearance of damaged cells by directing micronuclei rupture through lamin A/C phosphorylation and cGAS-STING pathway activation 3. Emerging evidence reveals ATR's non-canonical roles in stabilizing PINK1 for mitochondrial quality control 4 and phosphorylating OCT4 to safeguard human naive pluripotency 5. ATR dysfunction is associated with multiple cancers and Seckel syndrome. Proximal tubule ATR prevents maladaptive kidney repair responses following injury 6. ATR inhibitors are in clinical development as cancer therapeutics 17.