ATM functions and ataxia-telangectasia phenotypes

Ataxia-telangiectasia is a rare hereditary syndrome involving cerebellar degeneration, immunodeficiency, radiosensitivity and increased cancer risk. Since the cloning of the A-T gene, ATM, in 1995, research on this pleiotropic disease and its molecular basis has expanded tremendously. ATM is a 350kDa kinase protein that appears to be one of the primary sensors of DNA strand-break damage. Recent works showing the interaction of ATM with proteins involved in cell cycle control, and the direct phosphorylation of some of these proteins by ATM, have advanced our understanding of how the loss of a single 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 DNA ends. Others are the result of the systematic elimination of cells that have failed to respect cell cycle checkpoints, for example the extreme sensitivity to the lethal effects of irradiation. These hypotheses have to be demonstrated, and some clinical aspects observed in A-T patients remain to be explained, such as the telangiectasia and Purkinje cell degeneration.