Oxidant and environmental toxicant-induced effects compromise DNA ligation during base excision DNA repair

Çağlayan, Melike; Wilson, Samuel H.

doi:10.1016/j.dnarep.2015.09.010

Cited by 44 publications

(64 citation statements)

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“…In the present study, we examined the effects of pol β-mediated oxidized nucleotide insertion on downstream steps in the BER pathway. Our working model for BER suggests that after pol β fills the gap, the resulting nicked BER intermediate is passed to a DNA ligase for completion of repair23. Thus, the effect of oxidized nucleotide insertion on the ligation step is an important topic of investigation.…”

Section: Discussionmentioning

confidence: 99%

“…There is channelling of the repair intermediate after pol β nucleotide insertion to the final step in BER, DNA ligation, where a DNA ligase catalyzes phosphodiester bond formation between 3′-OH and 5′-P groups of the nicked BER intermediate2021. Since DNA ligase activity requires a natural annealed base pair at the 3′-margin of the nick22, mismatched or oxidized nucleotide insertion during the gap-filling step could result in disruption of BER23. However, the potential effect of oxidized base insertion on DNA ligation is not well understood.…”

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Oxidized nucleotide insertion by pol β confounds ligation during base excision repair

et al. 2017

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Oxidative stress in cells can lead to accumulation of reactive oxygen species and oxidation of DNA precursors. Oxidized purine nucleotides can be inserted into DNA during replication and repair. The main pathway for correcting oxidized bases in DNA is base excision repair (BER), and in vertebrates DNA polymerase β (pol β) provides gap filling and tailoring functions. Here we report that the DNA ligation step of BER is compromised after pol β insertion of oxidized purine nucleotides into the BER intermediate in vitro. These results suggest the possibility that BER mediated toxic strand breaks are produced in cells under oxidative stress conditions. We observe enhanced cytotoxicity in oxidizing-agent treated pol β expressing mouse fibroblasts, suggesting formation of DNA strand breaks under these treatment conditions. Increased cytotoxicity following MTH1 knockout or treatment with MTH1 inhibitor suggests the oxidation of precursor nucleotides.

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confidence: 99%

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Oxidized nucleotide insertion by pol β confounds ligation during base excision repair

et al. 2017

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“…It has been found that coordination between these BER enzymes is crucial and, when deficient, is associated with loss of cell viability and genomic stability [17, 19]. However, the mechanism of how unrepaired single-strand break intermediates are generated during the repair of endogenously and environmentally induced cytotoxic and mutagenic lesions is still under investigation [20, 21]. Left unrepaired, these blocked ends could interrupt BER, block replication and transcription, and be converted into toxic double-stranded breaks.…”

Section: Introductionmentioning

confidence: 99%

Role of DNA polymerase β oxidized nucleotide insertion in DNA ligation failure

Çağlayan

Wilson

2017

Journal of Radiation Research

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Production of reactive oxygen and nitrogen species (ROS), such as hydrogen peroxide, superoxide and hydroxyl radicals, has been linked to cancer, and these oxidative molecules can damage DNA. Base excision repair (BER), a major repair system maintaining genome stability over a lifespan, has an important role in repairing oxidatively induced DNA damage. Failure of BER leads to toxic consequences in ROS-exposed cells, and ultimately can contribute to the pathobiology of disease. In our previous report, we demonstrated that oxidized nucleotide insertion by DNA polymerase β (pol β) impairs BER due to ligation failure and leads to formation of a cytotoxic repair intermediate. Biochemical and cytotoxic effects of ligation failure could mediate genome stability and influence cancer therapeutics. In this review, we discuss the importance of coordination between pol β and DNA ligase I during BER, and how this could be a fundamental mechanism underlying human diseases such as cancer and neurodegeneration. A summary of this work was presented in a symposium at the International Congress of Radiation Research 2015 in Kyoto, Japan.

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“…If pol β were to insert an incorrectly matched or oxidatively damaged nucleotide into the gapped DNA, the resulting nicked product can potentially be passed on to DNA ligase III for nick sealing. However, the presence of the modified or mismatched base pair at the 3′-end of the nick could lead to ligation failure and formation of an abortive ligation product with a 5′-adenylate (5′-AMP) group (88–90). Furthermore, if pol β does not remove the 5′-dRP of an AP site using its lyase activity prior to the ligation step, DNA ligases can generate abortive ligation products with a 5′-adenylated dRP containing BER intermediate (78).…”

Section: Further Processing Of the Ap Sitementioning

confidence: 99%

“…This conformational change could possibly disrupt channeling of the substrate from pol β to DNA ligase in the BER pathway and consequently alter the normal coordination during repair. It is also conceivable that the BER intermediate possessing the 5′-AMP group could serve as a signaling mechanism to trigger recruitment of DNA end-processing enzymes (88). After end-processing, pol β would have another opportunity at the gap-filling is inserted, the DNA ligase would ideally be able to successfully join 5′-phosphate and 3′-OH groups to complete the repair.…”

Section: Further Processing Of the Ap Sitementioning

confidence: 99%

Base excision repair of oxidative DNA damage from mechanism to disease

Freudenthal¹

2017

Front Biosci

172

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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...

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Oxidant and environmental toxicant-induced effects compromise DNA ligation during base excision DNA repair

Cited by 44 publications

References 72 publications

Oxidized nucleotide insertion by pol β confounds ligation during base excision repair

Oxidized nucleotide insertion by pol β confounds ligation during base excision repair

Role of DNA polymerase β oxidized nucleotide insertion in DNA ligation failure

Base excision repair of oxidative DNA damage from mechanism to disease

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