Physiological stimuli using reactive oxygen species (ROS) as second messengers caused nucleotide‐specific base modifications in the hypoxic response element of the VEGF gene in lung vascular cells, with the 3′ guanine of the HIF‐1 DNA recognition sequence uniformly targeted. Modeling this effect by replacing the targeted guanine with an abasic site increased incorporation of HIF‐1 and the bi‐functional DNA repair enzyme and transcriptional coactivator, Ref‐1/Ape1, into the transcriptional complex and engendered more robust reporter gene expression. Oxidants generated in the context of physiological signaling thus affect nuclear DNA integrity and may facilitate gene expression by optimizing DNA‐protein interactions.—Ziel, K. A., Grishko, V., Campbell, C. C., Breit, J. F., Wilson, G. L., Gillespie, M. N. Oxidants in signal transduction: impact on DNA integrity and gene expression. FASEB J. 19, 387‐394 (2005)