Regulation of transcription is a delicate cellular process with many checkpoints along the path from DNA to protein that are modulated during oxidative and inflammatory stress. One possible modulator of gene expression occurs when stress results in oxidative modification of guanine (G) to 8-oxo-7,8-dihydroguanine (OG) in G-rich gene promoter elements. A curious feature of some oxidation prone G-rich elements is their ability to adopt non-canonical structures such as G-quadruplexes (G4s) and i-motifs in the strand opposite, or Z-DNA. Studies in our laboratory have found G oxidation to OG in certain promoter regions can regulate gene expression via a shift in the structure to a G4 non-canonical fold. The NEIL3 DNA repair gene promoter possesses a potential G4 sequence sensitive to oxidation that induces transcription. A plasmid with the potential NEIL3 B→G4 sequence driving a luciferase gene was transfected into mammalian cells and found to be activated under oxidative stress conditions. Studies in cellulo with OG synthesized into the reporter plasmid, as well as in vitro experiments on model sequences support the proposal of OG providing a target for the DNA repair protein OGG1 to activate the B→G4 switch. Once switched APE1 functions in the initial steps to upregulate gene expression. The findings provide molecular-level details addressing one point at which the NEIL3 gene is upregulated during oxidative stress. Examples in other potential G-rich structure-switching sequences, like Z-DNA, will provide additional data supporting OG as a regulatory epigenetic-like modification in DNA.

Base modifications in DNA non-canonical structures regulate transcription

2019 Fall National Meeting

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