Oxidative Modification of Guanine in a Potential Z-DNA-Forming Sequence of a Gene Promoter Impacts Gene Expression

One response to oxidation of guanine (G) to 8-oxo-7,8-dihydroguanine (OG) in a gene promoter is regulation of mRNA expression suggesting an epigenetic-like role for OG. A proposed mechanism involves G oxidation within a potential G-quadruplex-forming sequence (PQS) in the promoter, enabling a structural shift from B-DNA to a G-quadruplex fold (G4). When OG was located in the coding vs template strand, base excision repair led to an on/off transcriptional switch. Herein, a G-rich, potential Z-DNA-forming sequence (PZS) comprised of a d(GC)n repeat was explored to determine whether oxidation in this motif was also a transcriptional switch. Bioinformatic analysis found 1650 PZSs of length >10 nts in the human genome that were overrepresented in promoters and 5′-UTRs. Studies in human cells transfected with a luciferase reporter plasmid in which OG was synthesized in a PZS context in the promoter found that a coding strand OG increased expression and a template strand OG decreased expression. The initial base...