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Review
. 2011 Jun 15;14(12):2491-507.
doi: 10.1089/ars.2010.3466. Epub 2010 Oct 28.

Base excision repair and lesion-dependent subpathways for repair of oxidative DNA damage

David Svilar  1 , Eva M Goellner, Karen H Almeida, Robert W Sobol
Affiliations
Review

Base excision repair and lesion-dependent subpathways for repair of oxidative DNA damage

David Svilar et al. Antioxid Redox Signal. .

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 β-lyase activity; (b) monofunctional; and (c) bifunctional with an associated β,δ-lyase 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.

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Figures

FIG. 1.
FIG. 1.
Oxidative damage of 2′-deoxynucleotides. Structures of 2′-deoxyguanosine and the oxidatively modified DNA lesions 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) (A); 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapydG) (B); the LPO products N2,3-etheno-2′-deoxyguanosine (C); and 1,N2-etheno-2′-deoxyguanosine (D) (15, 19, 74). Structures of 2′-deoxyadenosine and the oxidatively modified DNA lesions 8-oxo-7,8-dihydro-2′-deoxyadenosine (8-oxodA) (E); 4,6-diamino-5-formamidopyrimidine (FapydA) (F); and the LPO product 1,N6-etheno 2′-deoxyadenosine (G) (15, 19, 74). Structures of 2′-deoxycytidine and the oxidatively modified DNA lesions 5-hydroxy-2′-deoxycytidine (OH5dC) (H); 5-hydroxy-2′-deoxyuridine (OH5dU) (I); 5,6-dihydro-2′-deoxyuridine (dHU) (J); and the LPO product 3,N4-ethenocytidine (K) (15, 19, 74). Structures of thymidine and the oxidatively modified DNA lesions thymine glycol (Tg) (L); 5-hydroxy-5,6-dihydrothymine (Th5) (M); and 5,6-dihydrothymine (dHT) (N) (15, 19). Structures of 5-methyl-2′-deoxycytidine and the oxidatively modified DNA lesion 5-(hydroxymethyl)-2′-deoxycytidine (hmdC) (O) (15). Where indicated, the R-group is 2′-deoxyribose.
FIG. 2.
FIG. 2.
Bifunctional DNA glycosylase (via β-elimination)–initiated BER pathway. Repair of oxidative base damage (e.g., 8-oxodG) initiated by the bifunctional DNA glycosylase OGG1. The chemistry of the lesion and the repair intermediates throughout the repair process are shown (center), highlighting the three essential steps for BER: lesion recognition/strand scission, gap tailoring, and DNA synthesis/ligation (left). The structures on the right depict the protein complexes required for completion of each step in BER initiated by OGG1.
FIG. 3.
FIG. 3.
The GO pathway. Diagrammatic representation of the repair and mutagenic consequences of 8-oxodG. Repair of 8-oxodG is mediated by OGG1-initiated BER (left). If not repaired, the replicative polymerases prefer to insert A opposite 8-oxodG. The incorrect A residue is repaired by MYH-initiated BER (center). However, if not repaired before a second round of replication (right), the 8-oxodG•A base pair is converted to another 8-oxodG•A base pair and an A•T base pair, inducing a G⇒T substitution mutation. Both the 8-oxodG•C base pair and 8-oxodG•A base pair can be repaired again, if needed (arrows).
FIG. 4.
FIG. 4.
Monofunctional DNA glycosylase–initiated BER pathway. Repair of adenosine when opposite the oxidative base lesion 8-oxodG, as initiated by the monofunctional DNA glycosylase MYH. The chemistry of the lesion and the repair intermediates throughout the repair process are shown (center), highlighting the three essential steps for BER: lesion recognition/strand scission, gap tailoring, and DNA synthesis/ligation (left). The structures on the right depict the protein complexes required for completion of each step in BER initiated by MYH.
FIG. 5.
FIG. 5.
Bifunctional DNA glycosylase (through β,δ-elimination)–initiated BER pathway. Repair of oxidative base damage (e.g., (5′R)-8,5′-cyclo-2′-deoxyadenosine) initiated by the bifunctional DNA glycosylase NEIL1. The chemistry of the lesion and the repair intermediates throughout the repair process are shown (center), highlighting the three essential steps for BER: lesion recognition/strand scission, gap tailoring, and DNA synthesis/ligation (left). The structures on the right depict the protein complexes required for completion of each step in BER initiated by NEIL1.
FIG. 6.
FIG. 6.
Model depicting the generation and consequences of ROS-mediated base damage. Reactive oxygen species are generated from multiple exogenous and endogenous sources, such as ultraviolet light, radiation, metal ions, cellular respiration, imbalance of cellular antioxidant systems, and phagocytes. ROS-generated DNA base lesions, such as 8-oxoG and FapyG, are subject to repair, initiated by lesion-specific DNA glycosylases (e.g., NEIL1, NEIL2, MYH, MBD4, NTHL1, OGG1, and UNG, as indicated). Recognition and repair of these lesions through the BER pathway results in enhanced cellular survival and genome maintenance. Inability to recognize or repair oxidative lesions leads to genomic instability, mitochondrial dysfunction, neurodegeneration, cancer, and aging. The consequences of unrepaired oxidative damage can result in a feedback loop generating additional ROS, leading to a cycle of increasing ROS and elevated genome instability.
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