DNA Glycosylases in Noncancer Diseases: Oxidative Lesion Recognition, Repair Intermediates, and Tissue Responses

Oxidative DNA damage in noncancer tissues can perturb transcription, compromise telomere integrity, and impair mitochondrial function. DNA glycosylases initiate base excision repair (BER), but their biological consequences also depend on lesion recognition, chromatin residence, catalytic processing, and the persistence or resolution of abasic sites and strand breaks. This review integrates structural and kinetic evidence with experimental models of inflammation, telomeric senescence, cardiometabolic disease, neurodegeneration, and neural injury. Promoter-associated 8-oxoguanine DNA glycosylase 1 (OGG1) can either promote inflammatory transcription or restrict antiviral interferon expression in a locus-dependent manner. At oxidatively damaged telomeres in human fibroblasts, OGG1 and mutY DNA glycosylase (MUTYH) drive acute senescence through repair intermediates, whereas during repeated injury, OGG1 supports telomere maintenance and MUTYH-dependent arrest limits chromosome instability. Mitochondria-directed OGG1 expression improves metabolic outcomes in OGG1-deficient mice exposed to a high-fat diet. By contrast, vascular and neural phenotypes associated with Nei-like DNA glycosylase 3 (NEIL3) remain difficult to attribute to a defined initiating lesion. These findings emphasize distinguishing enzyme occupancy, catalytic processing, and completed repair. Therapeutic studies should define the relevant cell, substrate, compartment, and exposure period and assess tissue function directly alongside unresolved lesions and chromosome stability.