Base Excision Repair and Lesion-Dependent Subpathways for Repair of Oxidative DNA Damage

Abstract

Nuclear and mitochondrial genomes are under continuous assault by a combination of environmentally and endogenously derived reactive oxygen species, inducing the formation and accumulation of mutagenic, toxic, and=or genome-destabilizing DNA lesions. Failure to resolve these lesions through one or more DNA-repair processes is associated with genome instability, mitochondrial dysfunction, neurodegeneration, inflammation, aging, and cancer, emphasizing the importance of characterizing the pathways and proteins involved in the repair of oxidative DNA damage. This review focuses on the repair of oxidative damage-induced lesions in nuclear and mitochondrial DNA mediated by the base excision repair (BER) pathway in mammalian cells. We discuss the multiple BER subpathways that are initiated by one of 11 different DNA glycosylases of three subtypes: (a) bifunctional with an associated b-lyase activity; (b) monofunctional; and (c) bifunctional with an associated b,dlyase activity. These three subtypes of DNA glycosylases all initiate BER but yield different chemical intermediates and hence different BER complexes to complete repair. Additionally, we briefly summarize alternate repair events mediated by BER proteins and the role of BER in the repair of mitochondrial DNA damage induced by ROS. Finally, we discuss the relation of BER and oxidative DNA damage in the onset of human disease.

Hydrogen peroxide mediated mitochondrial UNG1-PRDX3 interaction and UNG1 degradation

“…MtDNA is partially associated with the inner mitochondrial membrane, where the respiratory complexes catalyze oxidative phosphorylation and generate high levels of ROS which causes mtDNA damage [14][15][16]. Oxidative mtDNA damage can be repaired by both short-patch BER and long-patch BER [17][18][19], and UNG1 is involved in the repair process [20][21][22]. In addition to mtDNA, proteins responsible for mtDNA BER may also be a target of the high level of ROS since they are associated with the inner mitochondrial membrane where the respiratory complexes reside [23].…”

FOXO3 Transcription Factor Is Essential for Protecting Hematopoietic Stem and Progenitor Cells from Oxidative DNA Damage

“…Thus, modulations of ROS may be used therapeutically (7,8). Cells, with distinct kinetics, constantly repair oxidative damage using mainly the base excision repair (BER) pathway (9). The relatively low levels of endogenous ROS in HSC restrict damage to DNA (10); however, the impact of increasing ROS levels on HSC DNA remains relatively unexplored (11).…”

Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney

“…The activation of macrophages and recruitment of neutrophils to sites of I/R by intravascular danger signals results in the release of an arsenal of RONS capable of inducing DNA damage and lipid peroxidation, thus causing major collateral tissue damage. Base excision repair (BER), initiated by various DNA glycosylases, is critical for the repair of RONS-associated DNA damage, including oxidized, deaminated, and etheno (e)-adducted DNA bases (4,5). BER involves the orchestration of the following enzymatic steps: damaged bases are excised by DNA glycosylase, followed by cleavage of the DNA backbone at the resulting abasic site; DNA ends are trimmed to generate a 3′OH and 5′P; the gap is then filled by DNA polymerase and the remaining nick sealed by DNA ligase to complete BER (6, 7) (Fig.…”