Oxidative DNA damage is epigenetic by regulating gene transcription via base excision repair

Significance Damage to DNA bases due to oxidative stress is thought to be deleterious, leading to stalled replication forks and mutations. Similarly, folding of DNA strands into G-quadruplexes slows the progression of polymerases, requiring specialized helicases for unfolding before transcription. In the case of oxidative damage in a G-quadruplex–forming sequence of a promoter, we show that the presence of the DNA damage lesion 8-oxoguanine (OG) leads to an ∼300% increase in gene expression. This concept was demonstrated by chemical synthesis of a segment of the vascular endothelial growth factor ( VEGF ) or endonuclease III-like protein 1 ( NTHL1 ) promoter with a site specifically incorporated lesion in a reporter plasmid. This observation is direct evidence that OG represents an epigenetic modification and G-quadruplex–forming sequences can serve as sensors of oxidative stress.