ATM (Ataxia-Telangiectasia Mutated DNA Double-Strand Break Apical Kinase Gene)
ATM (ATM serine/threonine kinase; HGNC:795, NCBI Gene ID 472) is a human locus mapped to chromosome band 11q22.3 that encodes PI3K-related serine/threonine protein kinase ATM (3,056 aa; ~350 kDa; EC 2.7.11.1). ATM acts in MRN-complex sensing of DNA double-strand breaks -> H2AX, CHK2, p53 (TP53) & BRCA1 phosphorylation, together with ATR (Sister Replication-Stress PIKK Kinase Gene), TP53 (Phosphorylated at Ser15 by ATM), and BRCA1 (Homologous Recombination Substrate of ATM). Encodes the apical serine/threonine kinase ATM that senses DNA double-strand breaks and orchestrates genome-wide repair and cell-cycle checkpoints.
MRN-complex sensing of DNA double-strand breaks -> H2AX, CHK2, p53 (TP53) & BRCA1 phosphorylation
Clinical / Therapeutic Role
Biallelic LoF causes Ataxia-Telangiectasia; heterozygous LoF predisposes to breast, pancreatic & prostate cancer; synthetic lethal with PARP/ATR inhibitors
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 66-exon mega-gene spanning ~150 kb on chromosome 11q22.3, encoding a giant 3,056-amino-acid phosphatidylinositol 3-kinase-related kinase (PIKK) composed of an expansive N-terminal alpha-helical solenoid of HEAT repeats (which binds NBN/NBS1 of the MRE11-RAD50-NBS1 complex) and a C-terminal FAT-Kinase-FATC catalytic domain.
Cellular & Tissue Expression Profile: Ubiquitously expressed in the nucleus of all proliferating and post-mitotic cells (including cerebellar Purkinje and granule neurons, lymphocytes undergoing V(D)J and class-switch recombination, and germ cells in meiotic prophase).
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Exists in unstressed cells as an inactive homodimer; within seconds of ionizing radiation or topoisomerase cleavage generating a DNA double-strand break (DSB), recruitment to the MRE11-RAD50-NBS1 (MRN) complex and TIP60 acetylation at Lys3016 trigger intermolecular autophosphorylation at Ser1981 and dissociation into active ATM monomers, which phosphorylate >700 substrates on SQ/TQ motifs—including histone H2AX (forming gamma-H2AX repair foci), CHK2 (CHEK2), TP53 (at Ser15), MDM2 (at Ser395), BRCA1, and KAP1—to coordinate homologous recombination and non-homologous end joining.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Biallelic loss-of-function mutations cause autosomal recessive Ataxia-Telangiectasia (A-T), characterized by progressive cerebellar Purkinje degeneration and ataxia, oculocutaneous telangiectasias, IgA/IgG immunodeficiency, extreme radiosensitivity, and lymphoid malignancies; heterozygous germline pathogenic variants (carried by ~1% of the population) confer a 2- to 4-fold increased risk of female breast cancer and elevated risk of pancreatic and prostate adenocarcinoma.
Therapeutic & Clinical Pharmacology: Somatic or germline ATM-deficient tumors rely heavily on the sister kinase ATR and PARP1 for survival, rendering ATM-mutant cancers clinically sensitive to PARP inhibitors (olaparib, talazoparib) and selective ATR inhibitors (ceralasertib, berzosertib).