The Ataxia telangiectasia gene product is required for oxidative stress-induced G(1) and G(2) checkpoint function in human fibroblasts

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by neuronal degeneration accompanied by ataxia, telangiectasias, acute can cer predisposition, and sensitivity to ionizing radiation (IR). Cells from individuals with AT show unusual sensitivity to IR, severely attenuated cel l cycle checkpoint functions, and poor p53 induction in response to IR comp ared with normal human fibroblasts (NHFs), The gene mutated in AT (ATM) has been cloned, and its product, pATM, has IR-inducible kinase activity. The AT phenotype has been suggested to be a consequence, at least in part, of a n inability to respond appropriately to oxidative damage. To test this hypo thesis, we examined the ability of NHFs and AT dermal fibroblasts to respon d to t-butyl hydroperoxide and IR treatment. Ar fibroblasts exhibit, in com parison to NHFs, increased sensitivity to the toxicity of t-butyl hydropero xide, as measured by colony-forming efficiency assays. Unlike NHFs, AT fibr oblasts fail to show G(1) and G(2) phase checkpoint functions or to induce p53 in response to t-butyl hydroperoxide. Treatment of NHFs with t-butyl hy droperoxide activates pATM-associated kinase activity. Our results indicate that pATM is involved in responding to certain aspects of oxidative damage and in signaling this information to downstream effecters of the cell cycl e checkpoint functions. Our data further suggest that some of the pathologi es seen in AT could arise as a consequence of an inability to respond norma lly to oxidative damage.