ATM

Function

ATM exists in the nucleus as an inactive dimer. A double-strand break - from ionizing radiation, replication fork collapse, or telomere dysfunction - exposes DNA ends, the MRN complex (MRE11-RAD50-NBS1) binds them, and ATM monomerizes and autophosphorylates into an active kinase. Active ATM phosphorylates hundreds of substrates, the central ones being p53 (stabilizing it and producing arrest or apoptosis), CHK2 (amplifying the signal), H2AX (marking the damage site for repair machinery), and BRCA1. The result is a coordinated program: arrest, repair, and - if repair fails - senescence or death.

In cancer

The gene takes its name from ataxia telangiectasia, the recessive syndrome of cerebellar degeneration, immunodeficiency, radiation sensitivity, and early cancer incidence in homozygotes. Heterozygotes have elevated breast cancer risk. Because ATM loss lets damaged cells continue dividing, ATM behaves as a [tumor suppressor](Types of tumor suppressor genes.md), and its loss also sensitizes tumors to radiation and to drugs that create replication stress - a therapeutic window exploited in ATM-deficient tumors.

Notes

• Human gene symbol: ATM; UniProt Q13315; 3,056 amino acids; PI3K-related kinase (PIKK) family.