| 8-Oxoguanine, formed when reactive oxygen species react at the C8 position of guanine within either DNA or RNA, adopts two distinct pairing geometries depending on its glycosidic bond conformation: in the anti conformation it pairs with cytosine as in unmodified guanine, while in the syn conformation it uses a Hoogsteen edge to mispair with adenine, and this dual pairing capacity is the direct chemical basis for its mutagenic potential. Unrepaired 8-oxoguanine that has mispaired with adenine produces a G-to-T transversion, equivalent to C-to-A on the complementary strand, once DNA replication proceeds across the lesion, making 8-oxoguanine one of the most common oxidative mutagenic base lesions in the genome. Repair of this lesion proceeds through the base excision repair pathway, initiated when the bifunctional glycosylase OGG1 recognizes 8-oxoguanine paired with cytosine, cleaves the N-glycosidic bond to excise the damaged base, and performs a beta-elimination reaction that incises the phosphodiester backbone at the resulting apurinic site; the nick is then processed by APE1 and completed through short-patch or long-patch base excision repair. When 8-oxoguanine has already mispaired with adenine before repair occurs, a parallel glycosylase, MUTYH, recognizes this 8-oxoguanine-adenine mismatch, excises the inserted adenine rather than the oxidized guanine itself, and hands off to APE1 to complete MUTYH-initiated base excision repair, restoring the opportunity for correct cytosine insertion opposite the lesion. A third layer of defense operates at the nucleotide pool level, where MTH1 hydrolyzes oxidized guanine triphosphate before it can be incorporated into DNA by polymerases, preventing mutagenesis that would otherwise arise from direct incorporation of an already oxidized nucleotide rather than from in situ oxidation of genomic DNA. 8-oxoguanine also functions as an epigenetic signal: local reactive oxygen species generated during TET1-mediated DNA demethylation induce 8-oxoguanine formation at CpG islands, and the resulting 8-oxoguanine-OGG1 complex recruits repressive chromatin machinery, including DNA methyltransferases, to drive chromatin condensation and gene silencing at the damaged site. In RNA, the same oxidized base, denoted o8G, compromises translational fidelity and coding capacity, causes ribosome stalling and abortive protein products, and is subject to clearance through RNA decay pathways, extending 8-oxoguanine's functional relevance from mutagenesis and epigenetic regulation into post-transcriptional quality control, with accumulation of unrepaired 8-oxoguanine in either nucleic acid linked to aging, neurodegeneration, and cancer. |
