Oxidatively generated DNA base modifications: Relation to eustress and distress

Abstract Oxidative stress at the DNA, i.e., the generation of DNA damage by endogenously produced reactive oxygen species, is of particular concern as it can give rise to mutations and thereby an increased cancer risk. On the other hand, there is accumulating evidence that oxidized DNA bases, in particular 8-oxo-7,8-dihydroguanine (8-oxoG), are actively generated in mammalian cells as epigenetic marks and are involved in transcriptional regulation. To better understand this apparent paradox, this chapter first describes the types and mechanisms of DNA damage under conditions of exogenous and endogenous oxidative stress. It then summarizes the indications that oxidatively generated DNA damage and mutations contribute significantly to the overall human cancer risk, based on (i) the mutation spectra in cancer cells as obtained by whole genome sequencing, (ii) studies with repair-deficient mice, and (iii) the findings of repair defects in human cancers. Finally, the newly detected physiological role of 8-oxoG in the regulation of the transcription of certain genes is described and contrasted with the potential detrimental effects.