Ataxia-telangiectasia and the ATM gene: linking neurodegeneration, immunodeficiency, and cancer to cell cycle checkpoints.

ABSTRACT

Defects in regulation of the cellular life cycle may lead to premature cellular death or malignant transformation. Most of the proteins known to be involved in these processes are mediators of mitogenic signals or components of the cell cycle machinery. It has recently become evident, however, that systems responsible for ensuring genome stability and integrity are no less important in maintaining the normal life cycle of the cell. These systems include DNA repair enzymes and a recently emerging group of proteins that alert growth regulating mechanisms to the presence of DNA damage. These signals slow down the cell cycle while DNA repair ensues. Ataxia telangiectasia (A-T) is a genetic disorder whose clinical and cellular phenotype points to a defect in such a signaling system. A-T is characterized by neurodegeneration, immunodeficiency, 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 proliferation rates, are particularly sensitive to the absence of ATM function. The identification of the ATM gene highlights the growing importance of signal transduction initiated in the nucleus rather than in the external environment, for normal cellular growth.