ISOLATION OF FULL-LENGTH ATM CDNA AND CORRECTION OF THE ATAXIA-TELANGIECTASIA CELLULAR PHENOTYPE

A gene mutated in the human genetic disorder ataxia-telangiectasia (A- T), ATM, was recently identified by positional cloning, ATM is a membe r of the phosphatidyl-inositol-3-kinase superfamily, some of which are protein kinases and appear to have important roles in cell cycle cont rol and radiation signal transduction. We describe herein, to our know ledge, for the first time, the cloning of a full-length cDNA for ATM a nd correction of multiple aspects of the radio-sensitive phenotype of A-T cells by transfection with this cDNA, Overexpression of ATM cDNA i n A-T cells enhanced the survival of these cells in response to radiat ion exposure, decreased radiation-induced chromosome aberrations, redu ced radio-resistant DNA synthesis, and partially corrected defective c ell cycle checkpoints and induction of stress-activated protein kinase . This correction of the defects in A-T cells provides further evidenc e of the multiplicity of effector functions of the ATM protein and sug gests possible approaches to gene therapy.