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

Abstract

Reactive oxygen species (ROS) have emerged as important cellular signaling agents for survival. Herein, we demonstrate that ROS-mediated oxidation of DNA to yield 8-oxo-7,8dihydroguanine (OG) in gene promoters is a signaling agent for gene activation. Enhanced gene expression occurs when OG is formed in guanine-rich, potential G-quadruplex sequences (PQS) in promoter coding strands to initiate base excision repair (BER) by 8-oxoguanine DNA glycosylase (OGG1) yielding an abasic site (AP). The AP enables melting of the duplex to unmask the PQS to adopt a G-quadruplex fold in which apurinic/apyrimidinic endonuclease 1 (APE1) binds, but inefficiently cleaves, the AP for activation of VEGF or NTHL1 genes. This concept allowed identification of 61 human DNA repair genes that might be activated by this mechanism. Identification of the oxidatively-modified DNA base OG as guiding protein activity on the genome and altering cellular phenotype ascribes an epigenetic role to OG.

G-quadruplex–forming promoter sequences enable transcriptional activation in response to oxidative stress

“…Supporting this view is the fact that Fleming et al also provide a more comprehensive mechanistic explanation for the DNA oxidation and BER-dependent transcriptional activation reported in several cellular studies (4,10,11,21). In each case, the target gene investigated turned out to contain a PQS in its promoter (8).…”

“…As shown by the Barton group (22), redox electrons can "tunnel" through the pi-stacked bases of intact DNA duplex over distances of more than 200 Å. Intriguingly, the exits from such "tunnels" are often tracks of guanines, with the 5′-most guanine in a G track being most susceptible to oxidation (22). This mechanism may allow, at least initially, the focusing of a diffuse oxidative insult to select guanines in PQS in the genome, which, in light of the Fleming et al study (8), could initiate an oxidative stress-induced transcriptional response.…”

“…However, an emerging area of research posits that certain oxidative DNA lesions and their associated repair complexes are intermediates in a signaling transduction cascade that uses ROS as secondary messengers to ultimately effect transcriptional regulation (3)(4)(5)(6)(7). In PNAS, Fleming et al (8) reinforce these notions by describing a compelling mechanism by which 8-oxoguanine (OG), a canonical oxidative DNA damage product, when occurring in guanine-rich, G-quadruplex-forming promoter sequences, directly up-regulates transcription of the downstream gene.…”

“…Many of these sequences, when folded as G4s, can bind with high-affinity cellular proteins or transcription factors (16), but the relevance and physiological role of such interactions are still actively investigated. In PNAS, Fleming et al advance the hypothesis that a subset of these PQS can function as sensors of oxidative stress (8). Using the VEGF PQS sequence as a model, the authors provide a mechanistic connection between two previously known, but seemingly disparate characteristics of the VEGF promoter: (i) oxidative lesions (i.e., OG) in the promoter region lead to an increased expression level of VEGF; (ii) the promoter features a PQS composed of five guanine tracks (G tracks).…”

DNA damage and base excision repair : an important role during zebrafish embryogenesis

“…This provides a precedent that controlled DNA damage and repair can regulate active transcription. Other studies have also shown that site specific DNA damage can activate gene transcription (Ba et al 2014;Fleming, Ding, and Burrows 2017;Pan et al 2016;Pastukh et al 2015), though the mechanism through which damage occurs to specific points in the genome remains relatively unexplored.…”