ATM functions and ataxia-telangectasia phenotypes

Ataxia-telangiectasia is a rare hereditary syndrome involving cerebellar de generation, immunodeficiency, radiosensitivity and increased cancer risk. S ince the cloning of the A-T gene, ATM, in 1995, research on this pleiotropi c disease and its molecular basis has expanded tremendously. ATM is a 350kD a kinase protein that appears to be one of the primary sensors of DNA stran d-break damage. Recent works showing the interaction of ATM with proteins i nvolved in cell cycle control, and the direct phosphorylation of some of th ese proteins by ATM, have advanced our understanding of how the loss of a s ingle master regulator of genomic integrity results in this complex disease . Some disease symptoms are direct manifestations of the lack of DNA strand -break recognition. For example the characteristic chromosomal instability and the cancer risk may be a direct result of the abnormal processing of DN A ends. Others are the result of the systematic elimination of cells that h ave failed to respect cell cycle checkpoints, for example the extreme sensi tivity to the lethal effects of irradiation. These hypotheses have to be de monstrated, and some clinical aspects observed in A-T patients remain to be explained, such as the telangiectasia and Purkinje cell degeneration.