CHARACTERIZATION OF THE ATAXIA-TELANGIECTASIA GENE PRODUCT

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Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by oculocutaneous telangiectasias and progressive neuromotor dysfunction, cellular and humoral immune deficiencies, hypersensitivity to ionizing radiation and increased predisposition to leukemias and lymphomas. TheATM gene consists of a 13 kb transcript encoding a 3056 amino acid protein and shows homology in yeast, Drosophila , and other mammals to the catalytic subunit of phosphatidylinositol-3 kinase involved in the control of cell cycle progression and in cellular responses to DNA damage. Functional studies on the yeast homologs, TEL1 and MEC1, indicate that mutations in these genes give rise to cellular features similar to those observed in A-T cells. Similarly, the mouse Atm gene has been disrupted via gene targeting. Homozygous mice deficient in the Atm allele displayed growth retardation, neurologic dysfunction, infertility arising from failure to form mature gametes, defects in T lymphocyte maturation and extreme sensitivity to gamma-irradiation. Using an Ab developed for the ATM protein. Our additional findings indicate that the ATM protein is exclusively found in the nucleus of fibroblast cells and with an additional cofractionation of the protein with microsomes in lymphoblasts; that the ATM protein remains nuclear and not associated with any cellular structures at all stages in the cell cycle in fibroblasts; and the ATM protein expression is not induced by gamma-irradiation unlike that of p53.