Oxidized Guanine Base Lesions Function in 8-Oxoguanine DNA Glycosylase-1-mediated Epigenetic Regulation of Nuclear Factor κB-driven Gene Expression

Abstract

A large percentage of redox-responsive gene promoters contain evolutionarily conserved guanine-rich clusters; guanines are the bases most susceptible to oxidative modification(s). Consequently, 7,8-dihydro-8-oxoguanine (8-oxoG) is one of the most abundant base lesions in promoters and is primarily repaired via the 8-oxoguanine DNA glycosylase-1 (OOG1)-initiated base excision repair pathway. In view of a prompt cellular response to oxidative challenge, we hypothesized that the 8-oxoG lesion and the cognate repair protein OGG1 are utilized in transcriptional gene activation. Here, we document TNFα-induced enrichment of both 8-oxoG and OGG1 in promoters of pro-inflammatory genes, which precedes interaction of NF-κB with its DNA-binding motif. OGG1 bound to 8-oxoG upstream from the NF-κB motif increased its DNA occupancy by promoting an on-rate of both homodimeric and heterodimeric forms of NF-κB. OGG1 depletion decreased both NF-κB binding and gene expression, whereas Nei-like glycosylase-1 and -2 had a marginal effect. These results are the first to document a novel paradigm wherein the DNA repair protein OGG1 bound to its substrate is coupled to DNA occupancy of NF-κB and functions in epigenetic regulation of gene expression.

Unveiling the non-repair face of the Base Excision Repair pathway in RNA processing: A missing link between DNA repair and gene expression?

“…Hif1α, STAT1, NF-κB and MYC) in conjunction with OGG1 protein and, in turn, regulates the expression of important genes involved in cancer development, such as VEGF [40], SIRT-1 [41] and inflammatory genes such as TNF-α and CXCL2 [42]. Interestingly, this last role of OGG1 on inflammatory genes may explain the reduced inflammatory response in Ogg1 −/− mice [43].…”

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

“…Given the abundance of PQS in the promoter regions throughout the genome (12,13), the generality of the proposed mechanism may be very likely. 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).…”

“…Most oxidative DNA damage is efficiently processed by DNA repair pathways, primarily base excision repair (BER), the molecular details of which are generally well understood (2). 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.…”

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.…”

“…Likewise, oxidative damage to the vascular endothelial growth factor (VEGF) promoter enhances binding of hypoxiainducible factor 1a (HIF1a) with the subsequent assembly of BER components activating gene expression Ruchko 2009, 2010;Pastukh et al 2015). A similar process occurs in the promoters of tumor necrosis factor a (TNF-a) (Pan et al 2016) and sirtuin 1 (SIRT1) (Antoniali et al 2014). Controlled induction of gene transcription then requires activation of BER through OGG1…”