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.

Zika virus has emerged as a global concern because neither a vaccine nor antiviral compounds targeting it exist. A structure for the positive-sense RNA genome has not been established, leading us to look for potential G-quadruplex sequences (PQS) in the genome. The analysis identified >60 PQSs in the Zika genome. To minimize the PQS population, conserved sequences in the Flaviviridae family were found by sequence alignment, identifying seven PQSs in the prM, E, NS1, NS3, and NS5 genes. Next, alignment of 78 Zika strain genomes identified a unique PQS near the end of the 3`-UTR. Structural studies on the G-quadruplex sequences found four of the conserved Zika virus sequences to adopt stable, parallel-stranded folds that bind a G-quadruplex-specific compound, and one that was studied caused polymerase stalling when folded to a G-quadruplex. Targeting these PQSs with G-quadruplex binding molecules validated in previous clinical trials may represent a new approach for inhibiting viral replication.