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. 2021 Nov 7;10(11):3067. doi: 10.3390/cells10113067

Figure 2.

Figure 2

Models for OGG1-8-oxoGua-dependent gene expression. (A) Viral infection-induced ROS or those generated by cytokine exposure oxidatively modify guanine to 8-oxoGua and inactivate OGG1′ glycosylase activity by reversible oxidation at cysteine residues (cysteine-sulfenic acid). Oxidatively disabled OGG1 flips 8-oxoGua into its active-site pocket, interacts with the opposing cytosine and results in the conformational change of the DNA helix, which favors TFs DNA occupancy. (B) OGG1-8-oxoGua driven gene expression under hypoxic conditions. Guanines in gene promoters with G-quadruplexes are highly sensitive to ROS and are oxidized to 8-oxoGua under tissue hypoxia, caused by SARS-CoV-2, RSV, or H1N1 infections during pneumonia. OGG1 excises 8-oxoGua and generates an AP-site a substrate for APE1. APE1 binding leads to melting of the guanine duplex and stalls because of the non-canonical structure. Stalled APE1 increases transcription factor loading on the DNA via transient cooperative binding via conformational change of the helix. APE1, via its interacting domain, interacts with TFs (e.g., HIF1-α, STAT3, and CBP/p300) to modulate their redox state and promote both their binding to cis elements and gene expression. (C) OGG1-dependent transcription initiated by estrogens and its nuclear receptor. Estrogen (17β-estradiol; E2) binding to estrogen receptor alpha (ERα) results in demethylation of histone H3 lysine 9 (H3K9me2) via lysine-specific histone demethylase (LSD1; a flavin-dependent amine oxidase). Histone demethylation leads to a focal superoxide anion, hydroxyl radical generation and induces site-specific oxidation of guanine to 8-oxoGua. The latter is recognized and excised by OGG1 and via its AP-lyase activity cleave into the DNA strand generating the AP-site. The strand gap is recognized by topoisomerase II beta (topo IIb), which results in DNA structural changes in the chromatin allowing efficient assembly of transcriptional machinery and gene expression. Such scenarios are relevant to acute lung injury and SARS-CoV-2 infection capacity [138,139]. Similarly, LSD1-dependent DNA oxidation and OGG1 recruitment was needed for gene expression driven by TNFα, retinoic acid, and androgen exposure of cells [140,141,142]. Abbreviations: AP-site, apurinic/apyrimidinic site; APE-1, apurinic/apyrimidinic endonuclease 1; FAD, flavin adenine dinucleotide; FADH2, reduced flavin adenine dinucleotide; LSD1, flavin-dependent amine oxidase 1, 3-OH, 3-terminal hydroxyl; 5′-dRP, 5-terminal deoxyribose-phosphate.