Controlled DNA “damage” and repair in hypoxic signaling

Hypoxia, a fundamental stimulus in biology and medicine, uses reactive oxygen species (ROS) as second messengers. A surprising target of hypoxia-generated ROS is specific bases within hypoxic response elements (HREs) of the VEGF and other hypoxia-inducible genes. Oxidative modifications coincide with the onset of mRNA accumulation and are localized to transcriptionally active mono-nucleosomes. The oxidative base modifications are removed by the base excision DNA repair pathway for which one of its components, the bifunctional transcriptional co-activator and DNA endonuclease Ref-1/Ape1, is critical for transcription complex assembly. Mimicking the effect of hypoxia by introducing an abasic site in an oligonucleotide model of the VEGF HRE, altered transcription factor binding, enhanced sequence flexibility, and engendered more robust reporter gene expression. These observations suggest that controlled DNA “damage” and repair, mediated by ROS used as second messengers and critically involving the base excision pathway of DNA repair, respectively, are important for hypoxia-induced transcriptional activation.