Journal
RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY
Volume 174, Issue 3, Pages 244-251Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.resp.2010.08.025
Keywords
Hypoxia; Oxygen radicals; Oxidative DNA modifications; VEGF promoter; Transcriptional regulation
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Funding
- NHLBI NIH HHS [R21 HL083953, R01 HL073244, R21 HL083953-02, R01 HL058234, R01 HL058234-06, R01 HL073244-04] Funding Source: Medline
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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. (C) 2010 Elsevier B.V. All rights reserved,
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