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Oxidative DNA Modifications in Hypoxic Signaling
Author(s) -
Gillespie Mark N.,
Pastukh Viktor,
Ruchko Mykhaylo V.
Publication year - 2009
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2009.05036.x
Subject(s) - base excision repair , microbiology and biotechnology , transcription (linguistics) , biology , transcription factor , dna repair , dna damage , dna , gene , chemistry , biochemistry , linguistics , philosophy
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.