ATM, a paradigm for a stress-responsive signal transducer in higher vertebrate cells.

Abstract

ATM, the gene mutated in ataxia telangiectasia, is related to a family of large phosphatidylinositol 3-kinase domain-containing protein kinases involved in cell cycle control and DNA repair. To define the physiological roles of ATM in higher vertebrate cells, we created an ATM-deficient DT40 cell line, which, despite of the lack of p53 expression, displays multiple p53-independent defects in cell cycle checkpoint control and in maintenance of chromosomal DNA. ATM -/- DT40 cells also show a mild impairment in homologous recombination repair, which is independent of its checkpoint control defects. These ATM deficient DT40 clones thus provide a useful model system for analyzing p53-independent ATM functions in cellular response to double-strand break. Furthermore, we observe various abnormalities in cellular response to noxious stress such as oxidative stress in ATM -/- DT40 cells, indicating that ATM plays important roles not only in cellular response to DNA damage but also in the maintenance of the cell homeostasis in response to oxidative damage.