Cysteines of OGG1 are important for maintaining cellular homeostasis

Abstract

8-oxoguanine glycosylase (OGG1) is a base excision repair enzyme that recognizes and excises 8-oxoguanine, a commonly occurring oxidized DNA modification. OGG1 prevents the accumulation of mutations and regulates transcription of genes involved in inflammatory response, cancer growth, and angiogenesis. In addition to damaging DNA, oxidative stress can modify proteins like OGG1, specifically at cysteine residues. Previous work has shown that the function of OGG1 is sensitive to oxidants, with the cysteine residues of OGG1 being the most likely site of oxidation. Due to the integral role of OGG1 in maintaining cellular homeostasis under oxidative stress, it is important to understand the effect of oxidants on OGG1 and the role of cysteines in its structure and function. In this study, we investigate the role of the cysteine residues in the function of OGG1 by mutating and characterizing each cysteine residue. Our results indicate that the cysteines in OGG1 fall into four functional categories: those that are necessary for glycosylase activity, lyase activity, structural stability, and those with no known function. These results suggest that under conditions of oxidative stress, cysteines can be targeted for modifications, thus altering the response of OGG1 and affecting its ability to maintain cellular homeostasis. We hypothesize three scenarios in which cysteine modifications in OGG1 can result in decreased base excision repair, increased VEGF transcription, or increased CXCL2 and TNFα transcription. These changes in cellular homeostasis can result in cancer growth, angiogenesis, and metastasis.