ATM

About ATM

ATM Ataxia Telangiectasia Mutated on chromosome 11q22.3 encodes a large serine threonine kinase of the PI3K related kinase family that is the master regulator of the cellular response to DNA double strand breaks. After the MRN complex detects a break, ATM is activated and phosphorylates hundreds of substrates, including p53, CHK2, BRCA1, the histone variant H2AX, and KAP1, coordinating cell cycle checkpoints, DNA repair, and apoptosis. Variants on both copies of ATM cause ataxia telangiectasia, an autosomal recessive disorder with progressive cerebellar ataxia beginning in early childhood, dilated blood vessels in the eyes and skin, immunodeficiency with frequent infections, extreme sensitivity to ionizing radiation, and a high risk of lymphoma and leukemia. Elevated alpha fetoprotein is a characteristic laboratory finding. The gene was identified in 1995. Heterozygous carriers of pathogenic ATM variants have a moderately increased risk of breast cancer, roughly twofold, and an increased risk of pancreatic and prostate cancer, and ATM is included in multigene hereditary cancer panels. ATM deficient tumors may be sensitive to PARP inhibitors, and inhibitors of the related kinase ATR are being studied to exploit synthetic lethality with ATM loss.