Oxidative DNA modifications in hypoxic signaling.
Hypoxia, a fundamental biological stimulus, uses reactive oxygen species (ROS) as second messengers. Surprising molecular targets of hypoxia-generated ROS are the specific bases within hypoxic response elements (HREs) of the vascular endothelial growth factor (VEGF) and other hypoxia-inducible genes. Oxidative modifications coincide with the onset of mRNA accumulation and are localized to transcriptionally active mononucleosomes. The oxidative base modifications are removed, and the base excision DNA repair pathway is likely involved since Ref-1/Ape1, a transcriptional co-activator and DNA repair enzyme, is critical for transcription complex assembly. Mimicking the effect of hypoxia by introducing an abasic site in an oligonucleotide-based model of ROS-enhanced VEGF HRE sequence flexibility resulted in altered transcription factor binding and engendered more robust reporter gene expression. These observations suggest that controlled DNA "damage" and repair, mediated by ROS used as second messengers and by the base excision pathway of DNA repair, respectively, are important for hypoxia-induced transcriptional activation.
Department of Pharmacology, College of Medicine, University of South Alabama, Mobile, AL 36688-0002, USA. mgillesp@jaguar1.usouthal.edu
Mark N
MN
Gillespie
Viktor
V
Pastukh
Mykhaylo V
MV
Ruchko
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics; D011651:Pulmonary Artery / Q000166:cytology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A