DNA oxidation is a fundamental consequence of oxidative stress and a major determinant of genome instability, cellular senescence, and chronic disease. Although physiological concentrations of reactive oxygen species (ROS) participate in intracellular signaling and redox regulation, excessive ROS production disrupts redox homeostasis and promotes oxidative modification of nuclear and mitochondrial DNA. Endogenous ROS generated during mitochondrial oxidative phosphorylation represent the principal source of oxidative DNA injury, whereas chronic inflammation, transition metal-catalyzed reactions, ultraviolet radiation, ionizing radiation, cigarette smoke, environmental pollutants, hyperglycemia, and metabolic dysfunction further amplify genomic damage. Persistent oxidative injury is particularly detrimental in tissues with high metabolic activity or impaired antioxidant capacity, where continuous ROS exposure exceeds the efficiency of endogenous repair systems.
Oxidative attack on DNA generates a broad spectrum of lesions, including oxidized purines and pyrimidines, apurinic/apyrimidinic (AP) sites, DNA-protein crosslinks, single-strand breaks, double-strand breaks, and mitochondrial DNA damage. Among these lesions, 8-oxo-7,8-dihydroguanine (8-oxoG) and its nucleoside derivative 8-hydroxy-2′-deoxyguanosine (8-OHdG) are the best-characterized biomarkers of oxidative DNA damage because guanine possesses the lowest oxidation potential among DNA bases. Accumulation of 8-oxoG promotes GC→TA transversion mutations, alters transcription factor binding, and contributes to mutagenesis and genomic instability. Quantification of 8-OHdG in urine, plasma, serum, tissues, and circulating cell-free DNA has therefore become an important approach for evaluating oxidative stress in experimental and clinical research.
Maintenance of genomic integrity depends on an integrated DNA damage response (DDR) that coordinates lesion recognition, cell-cycle regulation, DNA repair, and, when necessary, apoptosis or senescence. Base excision repair (BER) constitutes the principal pathway for removing oxidized bases, particularly through the activity of 8-oxoguanine DNA glycosylase-1 (OGG1), which initiates excision of 8-oxoG lesions. Additional repair pathways, including nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR), and non-homologous end joining (NHEJ), correct structurally distinct DNA lesions and strand breaks. These mechanisms are orchestrated by ATM- and ATR-dependent checkpoint signaling together with p53, thereby preserving genome stability under oxidative challenge. Failure of these repair systems permits progressive mutation accumulation, telomere attrition, mitochondrial DNA instability, epigenetic dysregulation, and defective transcriptional control.
Oxidative DNA damage is closely integrated with redox signaling and inflammatory responses. Excess ROS activate NF-κB, MAPK, and inflammasome pathways while simultaneously stimulating NRF2, the master regulator of antioxidant defense. NRF2 activation induces genes involved in glutathione metabolism, NADPH regeneration, xenobiotic detoxification, and cellular antioxidant protection. However, persistent oxidative stress, defective DNA repair, and chronic inflammatory signaling can overwhelm these adaptive mechanisms, establishing a self-perpetuating cycle of genomic injury and cellular dysfunction. Consequently, oxidative DNA damage contributes to carcinogenesis, cardiovascular disease, diabetes mellitus, chronic kidney disease, neurodegenerative disorders, chronic liver disease, pulmonary disease, reproductive dysfunction, and biological aging.
Protection against oxidative genomic injury relies on an integrated antioxidant network comprising glutathione, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), thioredoxin, and peroxiredoxin systems. These pathways maintain intracellular redox balance and limit ROS-mediated DNA oxidation. Advances in clinical biochemistry, redox biomarker profiling, liquid biopsy, multi-omics, and precision redox medicine are expanding opportunities to integrate oxidative DNA biomarkers with genomic, transcriptomic, and metabolomic analyses. Such approaches may improve early diagnosis, disease stratification, therapeutic monitoring, and individualized interventions aimed at preserving genome stability and reducing oxidative stress-associated pathology.
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