DNA repair initiated by glycosylases in the nucleus and mitochondria of mammalian cells; how our cells respond to a flood of oxidative DNA damage

Abstract

Oxidative DNA damage causes blocks in transcription and replication and introduces errors leading to cell death and genomic instability. Extensive molecular analysis of repair mechanisms for oxidative DNA damage has revealed the strategy of mammalian cells against the threat posed by reactive oxygen species to the genetic information. Most oxidative base damage is first recognized by various glycosylases, which remove the base and initiate base excision repair, a repair mechanism widely distributed in life. However, disruptions of glycosylase genes have shown either no effect or rather mild phenotypes in mice, suggesting that the frontline defence against oxidative DNA damage has back-up systems. Indeed, a number of novel DNA glycosylases with overlapping substrate specificity were recently identified in mammalian cells. Several glycosylases are transported into the mitochondria too, indicating the importance of glycosylases and base damage repair in the mitochondria genome. Thus, mammalian cells survive the flood of oxidative DNA damage by means of extensive repair of the damage. Besides repair of DNA damage, mechanisms for tolerating DNA damage at replication have recently been discovered. Cells may tolerate residual damage at replication but thereby risk generating mutations.