Base excision repair of oxidative DNA damage from mechanism to disease

Abstract

Reactive oxygen species continuously assault the structure of DNA resulting in oxidation and fragmentation of the nucleobases. Both oxidative DNA damage itself and its repair mediate the progression of many prevalent human maladies. The major pathway tasked with removal of oxidative DNA damage, and hence maintaining genomic integrity, is base excision repair (BER). The aphorism that structure often dictates function has proven true, as numerous recent structural biology studies have aided in clarifying the molecular mechanisms used by key BER enzymes during the repair of damaged DNA. This review focuses on the mechanistic details of the individual BER enzymes and the association of these enzymes during the development and progression of human diseases, including cancer and neurological diseases. Expanding on these structural and biochemical studies to further clarify still elusive BER mechanisms, and focusing our efforts toward gaining an improved appreciation of how these enzymes form co-complexes to facilitate DNA repair is a crucial next step toward understanding how BER contributes to human maladies and how it can be manipulated to alter patient outcomes. KeywordsBase excision repair; Oxidative DNA damage; DNA repair; Review INTRODUCTION Oxidative DNA damageReactive oxygen species (ROS) are generated as a by-product of normal mitochondrial activity, these include superoxide, hydrogen peroxide, and the hydroxyl radical. The metabolic processes that generate ROS are essential for the cell, however a tradeoff is involved, and if not properly controlled the ROS concentration can exceed the antioxidant scavenging ability of the cell. Under this cellular condition, termed oxidative stress, ROS can cause extensive damage to cellular macromolecules. The structure of DNA is especially vulnerable to damage, and it has been estimated that DNA damage occurs at a rate of 10 4 Send correspondence to: Bret D. Freudenthal, 4015 WHW, Laboratory of Genome Maintenance and Structural Biology, Department of Biochemistry Molecular Biology, and Department of Cancer Biology, University of Kansas Medical Center Kansas, 66160, bfreudenthal@kumc.edu. HHS Public AccessAuthor manuscript Front Biosci (Landmark Ed). Author manuscript; available in PMC 2017 August 23. Published in final edited form as:Front Biosci (Landmark Ed). ; 22: 1493-1522. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript lesions/cell/day in humans, with oxidative DNA damage being particularly prevalent (1). Specifically, the structures of all four DNA nucleobases are susceptible to oxidative damage from ROS, with more than 100 different types of base damage being identified as products of oxidative stress (2). This base damage includes fragmented or ring-opened forms and oxidized aromatic derivatives. Several base lesions are highlighted in Figure 1 and discussed in more detail below. Generally, when the nucleobase structure is altered as the result of oxidative damage, its base-pairing properties are also altered, often leading to either...

APE1: A skilled nucleic acid surgeon

“…In addition to its role in surgically removing DNA damage, APE1 is also a redox factor and involved in both RNA metabolism and antibody class switch recombination [ 91 , 104 ]. Disruptions in the multifarious biological functions associated with APE1 can be linked with various human pathologies such as cancer and neurodegenerative diseases [ 12 , 13 ]. Since APE1 has roles in both disease suppression and therapeutic agent resistance, it is apparent that if APE1 DNA repair activities can be strategically regulated that the protein would be a potentially druggable target in both preventative and therapeutic treatments.…”

“…1 ). For a more detailed discussion of BER, its protein components, and its relationship to human disease, we direct the readers to the following references [ 12 , 13 ].

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DNA Damage/Repair Management in Cancers

“…DNA AP endonuclease or a DNA AP lyase cleaves the DNA backbone, and the activity of AP endonuclease produces a single-stranded DNA nick 5' to the AP site, while the activity of DNA AP lyase generates parallel nick 3' to the AP site [88]. In addition, AP endonuclease generates a new nick causing a single-nucleotide gap in the DNA causing 3'-hydroxyl and a 5'-phosphate [90].…”

“…Sometimes, the BER pathway fails to identify damage and when this lesion serves as a template during DNA synthesis, replicative DNA polymerases predominantly mis-merge dAMP at the primer terminus, causing mutations which may result in developing later diseases (Figure 3) [92]. causing a single-nucleotide gap in the DNA causing 3'-hydroxyl and a 5'-phosphate [90]. The polymerase fills the gap in the DNA by adding the correct nucleotides and the repairing mechanism completes the helical DNA shape, which is maintained after sealing the nick by a DNA ligase [82].…”

Genetic variation in the NEIL2 DNA glycosylase gene is associated with oxidative DNA damage in BRCA2 mutation carriers

“…If they are not repaired, these lesions may evolve into mutation (C:G→T transversions [ 12 ] or DNA single-strand [ 7 ] or double-strand breaks (DSBs) [ 13 , 14 ], which are the principal source of genomic instability [ 15 , 16 ].…”