ACTIVATION OF APURINIC APYRIMIDINIC ENDONUCLEASE IN HUMAN-CELLS BY REACTIVE OXYGEN SPECIES AND ITS CORRELATION WITH THEIR ADAPTIVE RESPONSETO GENOTOXICITY OF FREE-RADICALS/

Apurinic/apyrimidinic (AP) endonuclease (APE; EC 4.2.99.18) plays a ce ntral role in repair of DNA damage due to reactive oxygen species (ROS ) because its DNA 3'-phosphoesterase activity removes 3' blocking grou ps in DNA that are generated by DNA glycosylase/AP-lyases during remov al of oxidized bases and by direct ROS reaction with DNA. The major hu man APE (APE-1) gene is activated selectively by sublethal levels of a variety of ROS and ROS generators, including ionizing radiation, but not by other genotoxicants-e.g., UV light and alkylating agents. Incre ased expression of APE mRNA and protein was observed both in the HeLa S3 tumor line and in WI 38 primary fibroblasts, and it was accompanied by translocation of the endonuclease to the nucleus. ROS-treated cell s showed a significant increase in resistance to the cytotoxicity of s uch ROS generators as H2O2 and bleomycin, but not to UV light. This '' adaptive response'' appears to result from enhanced repair of cytotoxi c DNA lesions due to an increased activity of APE-1, which may be limi ting in the base excision repair process for ROS-induced toxic lesions .