Ataxia-telangiectasia: is ATM a Sensor of Oxidative Damage and Stress?

Ataxia-telangiectasia (A-T) is a pleiotropic recessive disorder characterized by cerebellar ataxia, immunodeficiency, specific developmental defects, profound predisposition to cancer and acute radiosensitivity. Functional inactivation of a single gene product, ATM, accounts for this compound phenotype. We suggest that ATM acts as a sensor of reactive oxygen species and/or oxidative damage of cellular macromolecules, including DNA. In turn, ATM induces signalling through multiple pathways, thereby coordinating acute phase stress responses with cell cycle checkpoint control and repair of oxidative damage. Absence of ATM is proposed to limit the repair of insidious oxidative damage that can occur under normal physiological conditions, ultimately leading to apoptosis of particularly sensitive cells, such as neurons and thymocytes.