Enhanced mitochondrial DNA repair of the common disease-associated variant, Ser326Cys, of hOGG1 through small molecule intervention

• Published in: Free radical biology & medicine Vol. 124; pp. 149 - 162
• Main Authors: Baptiste, Beverly A., Katchur, Steven R., Fivenson, Elayne M., Croteau, Deborah L., Rumsey, William L., Bohr, Vilhelm A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-08-2018
• Subjects: 8-dihydroguanine; 8-oxo-7; 8-Oxoguanine DNA glycosylase-1; A549 Cells; Animals; Base excision repair; Cells, Cultured; DNA Damage; DNA Glycosylases - genetics; DNA Glycosylases - metabolism; DNA Glycosylases - physiology; DNA Repair; DNA, Mitochondrial - genetics; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Herbicides - adverse effects; Humans; Mice; Mice, Knockout; Mitochondria; Mitochondria - drug effects; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; Mutation; OGG1S326C; Oxidation-Reduction; Oxidative stress; Oxidative Stress - drug effects; Paraquat - adverse effects; Reactive Oxygen Species - metabolism; Serine - genetics; Serine - metabolism; Small Molecule Libraries - pharmacology; 8-oxo-7; PQ; Oxidative stress; APE1; DMSO; 8-Oxoguanine DNA glycosylase-1; Base excision repair; OGG1S326C; 8-oxodG; AP; MEF; 8-oxoGua; MMP; 8-dihydroguanine; Mitochondria; FRET; OGG1(S326C)
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2018.05.094

The common oxidatively generated lesion, 8-oxo-7,8-dihydroguanine (8-oxoGua), is removed from DNA by base excision repair. The glycosylase primarily charged with recognition and removal of this lesion is 8-oxoGuaDNA glycosylase 1 (OGG1). When left unrepaired, 8-oxodG alters transcription and is mutagenic. Individuals homozygous for the less active OGG1 allele, Ser326Cys, have increased risk of several cancers. Here, small molecule enhancers of OGG1 were identified and tested for their ability to stimulate DNA repair and protect cells from the environmental hazard paraquat (PQ). PQ-induced mtDNA damage was inversely proportional to the levels of OGG1 expression whereas stimulation of OGG1, in some cases, entirely abolished its cellular effects. The PQ-mediated decline of mitochondrial membrane potential or nuclear condensation were prevented by the OGG1 activators. In addition, in Ogg1-/- mouse embryonic fibroblasts complemented with hOGG1S326C, there was increased cellular and mitochondrial reactive oxygen species compared to their wild type counterparts. Mitochondrial extracts from cells expressing hOGG1S326C were deficient in mitochondrial 8-oxodG incision activity, which was rescued by the OGG1 activators. These data demonstrate that small molecules can stimulate OGG1 activity with consequent cellular protection. Thus, OGG1-activating compounds may be useful in select humans to mitigate the deleterious effects of environmental oxidants and mutagens.
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•The OGG1 S326C variant has a mitochondrial defect in both 8-oxo-dG incision activity and superoxide accumulation.•In cells expressing only human OGG1 variant, the 8-oxo-dG incision defect can be rescued by small molecule intervention.•Small molecule stimulation of OGG1 decreases 8-oxo-dG accumulation in human cells in response to exogenous oxidation.