The OGG1 Ser326Cys polymorphism: molecular mechanisms of disease susceptibility and precision medicine applications.

Abstract

DNA molecules are susceptible to reactive oxygen species (ROS) attack leading to oxidative damage, of which 8-oxoguanine (8-oxoG) is a core oxidative marker. OGG1 acts as a DNA repair enzyme and maintains genomic stability by specifically repairing 8-oxoG through the base excision repair (BER) pathway. The Ser326Cys polymorphism significantly reduces enzyme activity and potentially impacts phosphorylation-mediated subcellular localization dynamics and epigenetic regulatory networks, thereby potentially exacerbating genomic instability. In this review, we analyzed the association between the OGG1 Ser326Cys polymorphism and different diseases, such as risk, platinum-based chemotherapy sensitivity, and radiotherapy toxicity in cancer. In neurodegenerative disorders, the Cys326 type leads to the accumulation of 8-oxoG in neurons and accelerates CAG triplet repeat amplification. In metabolic disorders, its insufficient repair may trigger β-cell dysfunction, which increases the risk of type 2 diabetes mellitus. Finally, we integrated multiomics data and proposed a genotype-based precision intervention strategy to provide a theoretical basis for disease risk prediction, personalized therapy, and novel targeted drug development.