Ataxia-telangiectasia: chronic activation of damage-responsive functions is reduced by alpha-lipoic acid

Cells from patients with the genetic disorder ataxia-telangiectasia (A-T) a re hypersensitive to ionizing radiation and radiomimetic agents, both of wh ich generate reactive oxygen species capable of causing oxidative damage to DNA and other macromolecules. We describe in A-T cells constitutive activa tion of pathways that normally respond to genotoxic stress, Basal levels of p53 and p21(WAF1/CIP1), phosphorylation on serine 15 of p53, and the Tyr15 -phosphorylated form of cdc2 are chronically elevated in these cells. Treat ment of A-T cells with the antioxidant alpha -lipoic acid significantly red uced the levels of these proteins, pointing to the involvement of reactive oxygen species in their chronic activation. These findings suggest that the absence of functional ATM results in a mild but continuous state of oxidat ive stress, which could account for several features of the pleiotropic phe notype of A-T.