ATR (Ataxia-Telangiectasia and Rad3-Related Replication-Stress Kinase Gene)
ATR (ATR checkpoint kinase; HGNC:882, NCBI Gene ID 545) is a human locus mapped to chromosome band 3q23 that encodes PI3K-related serine/threonine protein kinase ATR (2,644 aa; ~301 kDa; EC 2.7.11.1). ATR acts in RPA-coated single-stranded DNA sensing at stalled replication forks -> ATRIP-TOPBP1/ETAA1 -> CHK1 (CHEK1) activation, together with ATM (Double-Strand Break Sister Kinase Gene), BRCA1 (Replication Fork Protection Partner Gene), and BRCA2 (RAD51 Loading & Fork Protection Gene). Encodes the essential replication-stress kinase ATR that senses RPA-coated single-stranded DNA to stabilize stalled DNA replication forks.
RPA-coated single-stranded DNA sensing at stalled replication forks -> ATRIP-TOPBP1/ETAA1 -> CHK1 (CHEK1) activation
Clinical / Therapeutic Role
Hypomorphic biallelic mutations cause Seckel syndrome type 1; oncology target of ATR inhibitors (ceralasertib, camonsertib) in ATM/BRCA-mutant tumors
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 47-exon gene spanning ~130 kb on chromosome 3q23, encoding a 2,644-amino-acid PIKK family kinase featuring N-terminal HEAT repeats (which constitutively bind its obligate partner subunit ATRIP) and a C-terminal FAT-Kinase-FATC domain.
Cellular & Tissue Expression Profile: Essential in all dividing mammalian cells during S and G2 phases of the cell cycle, where it safeguards genome duplication across billions of base pairs.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Whereas ATM responds primarily to blunt DNA double-strand breaks throughout the cell cycle, ATR is recruited via ATRIP whenever helicase-polymerase uncoupling at stalled replication forks or 5-prime-to-3-prime resection of DSBs exposes single-stranded DNA (ssDNA) coated by Replication Protein A (RPA); subsequent engagement of allosteric activators TOPBP1 (at 9-1-1 clamp junctions) or ETAA1 activates ATR to phosphorylate CHK1 (CHEK1 at Ser317/Ser345), RPA2, WRN, and BRCA1—suppressing late origin firing, stabilizing replisomes to prevent fork collapse, and halting mitotic entry via CDC25A degradation.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Complete loss of ATR is early embryonically lethal in mammals because S-phase cells undergo catastrophic replication fork breakage (mitotic catastrophe); rare biallelic hypomorphic splicing or missense mutations in human ATR (such as the synonymous c.2101A>G exon 9 skipping allele) cause Seckel syndrome type 1, an autosomal recessive bird-headed primordial dwarfism with severe microcephaly.
Therapeutic & Clinical Pharmacology: Because oncogene-driven tumors (MYC, CCNE1 amplification) and ATM-, BRCA1/2-, or ARID1A-deficient cancers experience severe chronic replication stress, clinical ATR inhibitors (ceralasertib / AZD6738, berzosertib, camonsertib) selectively trigger mitotic catastrophe in cancer cells.