ATAXIA-TELANGIECTASIA AND THE ATM GENE - LINKING NEURODEGENERATION, IMMUNODEFICIENCY, AND CANCER TO CELL-CYCLE CHECKPOINTS

Defects in regulation of the cellular life cycle may lead to premature cellular death or malignant transformation. Most of the proteins know n to be involved in these processes are mediators of mitogenic signals or components of the cell cycle machinery. It has recently become evi dent, however, that systems responsible for ensuring genome stability and integrity are no less important in maintaining the normal life cyc le of the cell. These systems include DNA repair enzymes and a recentl y emerging group of proteins that alert growth regulating mechanisms t o the presence of DNA damage. These signals slow down the cell cycle w hile DNA repair ensues. Ataxia-telangiectasia (A-T) is a genetic disor der whose clinical and cellular phenotype points to a defect in such a signaling system. A-T is characterized by neurodegeneration, immunode ficiency, radiosensitivity, cancer predisposition, and defective cell cycle checkpoints. The responsible gene, ATM, was recently cloned and sequenced. ATM encodes a large protein with a region highly similar to the catalytic domain of PI 3-kinases. The ATM protein is similar to a group of proteins in various organisms which are directly involved in the cell cycle response to DNA damage. It is expected to be part of a protein complex that responds to a specific type of DNA strand break by conveying a regulatory signal to other proteins. Interestingly, the immune and nervous systems, which differ markedly in their proliferat ion rates, are particularly sensitive to the absence of ATM function. The identification of the ATM gene highlights the growing importance o f signal transduction initiated in the nucleus rather than in the exte rnal environment, for normal cellular growth.