APE/Ref-1 and the mammalian response to genotoxic stress

Human apurinic/apyrimidinic endonuclease/redox factor-1 (hAPE/Ref-1) is a multifunctional protein involved in the repair of DNA damaged by oxidative or alkylating compounds as well as in the regulation of stress inducible transcription factors such as AP-1, NF-kappaB, HIF-1 and p53. With respect to transcriptional regulation, both redox dependent and independent mechanisms have been described. APE/Ref-1 also acts as a transcriptional repressor. Recent data indicate that APE/Ref-1 negatively regulates the activity of the Ras-related GTPase Rac1. How these different physiological activities of APE/Ref-1 are coordinated is poorly understood. So far, convincing evidence is available that the expression of the APE/Ref-1 gene is inducible by oxidative stress and that overexpressed APE/Ref-1 protein protects cells against the genotoxic and cell killing effects of reactive oxygen species (ROS), whereas down-regulation sensitizes cells. Therefore, APE/Ref-1 can be considered to be part of an adaptive cellular response mechanism to oxidative genotoxic stress. The physiological relevance of increase of either the repair or redox activity of APE/Ref-1 for this adaptive response is unclear. Data will be shown that transfection of the truncated protein exhibiting either one of the activities provoked increase of resistance. Since APE/Ref-1 expression level and intracellular localization is variable in different types of tumors and frequently found to be different in non-malignant compared to the corresponding malignant human tissue, the protein is thought to be a diagnostic and prognostic tumor marker. Because of its involvement in DNA repair and apoptosis-related signaling mechanisms, APE/Ref-1 is also being discussed as a novel target for tumor-therapeutic approaches.