Fragments of ATM which have dominant-negative or complementing activity

The ATM protein has been implicated in pathways controlling cell cycle checkpoints, radiosensitivity, genetic instability, and aging. Expression of ATM fragments containing a leucine zipper motif in a human tumor cell line abrogated the S-phase checkpoint after ionizing irradiation and enhanced radiosensitivity and chromo-somal breakage. These fragments did not abrogate irradiation-induced G1 or G2 checkpoints, suggesting that cell cycle checkpoint defects alone cannot account for chromosomal instability in ataxia telangiectasia (AT) cells. Expression of the carboxy-terminal portion of ATM, which contains the PI-3 kinase domain, comple-mented radiosensitivity and the S-phase checkpoint and reduced chromosomal breakage after irradiation in AT cells. These observations suggest that ATM function is dependent on interactions with itself or other proteins through the leucine zipper region and that the PI-3 kinase domain contains much of the significant activity of ATM. Ataxia telangiectasia (AT) is a rare human autosomal reces-sive disorder with a wide variety of phenotypic manifestations. AT patients exhibit progressive cerebellar ataxia with degen-eration of Purkinje cells, oculocutaneous telangiectases, hyper-sensitivity to ionizing radiation (IR) and radiomimetic drugs