ATM: A mediator of multiple responses to genotoxic stress

The ATM protein kinase is the product of the gene responsible for the pleio tropic recessive disorder ataxia-telangiectasia. ATM-deficient cells show e nhanced sensitivity and greatly reduced responses to genotoxic agents that generate DNA double strand breaks (DSBs), such as ionizing radiation and ra diomimetic chemicals, but exhibit normal responses to DNA adducts and base modifications induced by other agents. Therefore, DSBs are most likely the predominant signal for the activation of ATM-mediated pathways. Identificat ion of the ATM gene triggered extensive research aimed at elucidating the n umerous functions of its large multifaceted protein product. While ATM has both nuclear and cytoplasmic functions, this review will focus on its roles in the nucleus where it plays a central role in the very early stages of d amage detection and serves as a master controller of cellular responses to DSBs. By activating key regulators of multiple signal transduction pathways , ATM mediates the efficient induction of a signaling network responsible f or repair of the damage, and for cellular recovery and survival.