Repair of Hydantoin Lesions and Their Amine Adducts in DNA by Base and Nucleotide Excision Repair

McKibbin, Paige L.; Fleming, Aaron M.; Towheed, Atif; Houten, Bennett Van; Burrows, Cynthia J.; David, Sheila S.

doi:10.1021/ja4059469

Cited by 54 publications

(80 citation statements)

References 95 publications

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“…All three lesions, NIm, Gh, and Sp, cause significant thermodynamic destabilization of DNA duplexes (21,25,26,(82)(83)(84)(85)(86)(87), which is a common feature of DNA substrates that are recognized by the NER machinery. Thus, the Sp and Gh lesions are recognized by the prokaryotic UvrABC nuclease (40) as well as by the eukaryotic NER machinery in human cell extracts as demonstrated here. However, the NER resistance of NIm appears to be correlated not with a destabilization but with its conformational flexibility in double-stranded DNA (26).…”

Section: Reaction1supporting

confidence: 57%

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Base and Nucleotide Excision Repair of Oxidatively Generated Guanine Lesions in DNA

Shafirovich

Kropachev

Anderson

et al. 2016

Journal of Biological Chemistry

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The well known biomarker of oxidative stress, 8-oxo-7,8-dihydroguanine, is more susceptible to further oxidation than the parent guanine base and can be oxidatively transformed to the genotoxic spiroiminodihydantoin (Sp) and 5-guanidinohydantoin (Gh) lesions. Incubation of 135-mer duplexes with single Sp or Gh lesions in human cell extracts yields a characteristic nucleotide excision repair (NER)-induced ladder of short dual incision oligonucleotide fragments in addition to base excision repair (BER) incision products. The ladders were not observed when NER was inhibited either by mouse monoclonal antibody (5F12) to human XPA or in XPC ؊/؊ fibroblast cell extracts. The overproduction of free radical intermediates and electrophiles by macrophages and neutrophils activated during the inflammatory response in chronically inflamed tissues induces persistent damage to cellular DNA (1). If not properly repaired, this DNA damage can increase levels of mutations and genomic instability and eventually can lead to the initiation of human cancers (2-4). The primary target of oxidatively generated DNA damage is guanine (5), the most easily oxidizable natural nucleic acid base (6). The best known oxidation product of guanine is 8-oxo-7,8-dihydroguanine (8-oxoG), 3 which is ubiquitous in cellular DNA and is used widely as a biomarker of oxidative stress (7). The 8-oxoG lesion is genotoxic, and failure to remove 8-oxoG before replication induces G:C 3 T:A transversion mutations (8). This lesion is even more easily oxidized than the parent base guanine (9), and its further oxidation by various oxidizing agents, including peroxynitrite, leads to the formation of stereoisomeric spiroiminodihydantoin (Sp) and 5-guanidinohydantoin (Gh) lesions (10 -15). In the case of guanine oxidation by peroxynitrite, the 5-guanidino-4-nitroimidazole (NIm) lesion (16 -18) is also produced and can serve as a biomarker of inflammation-related oxidation mechanisms (1). The NIm lesions together with the easily depurinated 8-nitroguanine, are typical products of guanine damage in calf thymus DNA induced by reactions with nitrosoperoxycarbonate (16, 19) derived from the combination of carbon dioxide and peroxynitrite (20). The structures of these oxidatively generated guanine lesions are shown in Fig. 1A.The chiral carbons in the Gh and Sp nucleobases give rise to a pair of R and S diastereomers. Oligonucleotides that contain single, site-specifically inserted Gh or Sp lesions can be separated and purified by anion-exchange HPLC methods (21). In aqueous solutions, the Gh diastereomers are easily interconvertible, and it is, therefore, not feasible to study their characteristics individually (22). In contrast, the Sp-S and Sp-R diastereomers are chemically stable and can be purified and studied individually (10,23). NMR structural studies in solution indicate that both stereoisomerically distinct Sp lesions (24) perturb adjacent base pairs and thus thermodynamically destabilize oligonucleotide duplexes (25). Molecular modeling studies indicate that the ...

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Section: Reaction1supporting

confidence: 57%

“…In vitro, the hydantoin lesions are efficiently repaired by base excision repair (BER) enzymes that include the E. coli Fpg (30), Nei (31), mammalian NEIL1 and NEIL2 (32), NEIL3 (33)(34)(35)(36), human NEIL1 (37,38), and NEIL3 (39) DNA glycosylases and by the prokaryotic nucleotide excision (NER) mechanism initiated by UvrABC proteins (40).…”

mentioning

confidence: 99%

Base and Nucleotide Excision Repair of Oxidatively Generated Guanine Lesions in DNA

Shafirovich

Kropachev

Anderson

et al. 2016

Journal of Biological Chemistry

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“…In such a case, the NER pathway may have to be involved as indicated by McKibbin et al. 10 The nucleophilic addition by an active-site lysine to the C1ʹ of the nucleobase-harbored Schiff base intermediate leads to the formation of a nucleoprotein intermediate. Such a species was trapped by NaBH 4 treatment and characterized in a number of DNA glycosylases including endonuclease III, FPG, and Nei.…”

Section: Discussionmentioning

confidence: 99%

Reactivity of Damaged Pyrimidines: Formation of a Schiff Base Intermediate at the Glycosidic Bond of Saturated Dihydrouridine

et al. 2015

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DNA glycosylases catalyze the first step of the base excision repair (BER) pathway. The chemistry used by these enzymes for deglycosylation has been largely considered as the chemistry of the oxocarbenium ion, e.g., direct rupture of the C1'-N1 bond resulting in an oxocarbenium ion intermediate. Here we present mechanistic studies revealing the 2'-deoxyribose isomerization and subsequent deglycosylation processes in two pyrimidine lesions: 5,6-dihydro-2'-deoxyuridine (dHdU) and 5,6-dihydrothymidine (dHT), formed via ionizing radiation damage to 2'-deoxycytidine and thymidine, respectively, under anoxic conditions. Acid or heat treatment of these two lesions leads to the production of two pairs of C1' epimers containing a pyranose and a furanose, respectively, indicating that both lesions favor the rupture of the C1'-O4' bond, resulting in a Schiff base intermediate at the N-glycosidic bond. Such a Schiff base intermediate was trapped and characterized by either Pd-catalyzed hydrogenation or thiol-mediated addition reaction. In contrast, in undamaged 2'-deoxyuridine and thymidine, reactions at elevated temperatures lead to the release of nucleobases most likely via the traditional oxocarbenium ion pathway. DFT calculations further support the experimental findings, suggesting that the oxocarbenium ion intermediate is responsible for the deglycosylation process if the integrity of the pyrimidine ring is maintained, while the Schiff base intermediate is preferred if the C5═C6 bond is saturated. Currently, the oxocarbenium ion pathway is indicated to be solely responsible for the deglycosylation in BER enzymes, however our results suggest an alternative Schiff base mechanism which may be responsible for the repair of saturated pyrimidine damages.

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“…The hydantoins in ssODNs, dsODNs, as bulges, or in G-quadruplex contexts are excellent substrates for the NEIL family of DNA glycosylases that initiate base excision repair, 70–73 in addition to being substrates for nucleotide excision repair. 73,74 However, studies to determine if hydantoins as part of a tandem lesion impact the repair pathway have not been conducted. On the basis of the T m studies in the present work (Fig.…”

Section: Discussionmentioning

confidence: 99%

8-Oxo-7,8-dihydro-2′-deoxyguanosine and abasic site tandem lesions are oxidation prone yielding hydantoin products that strongly destabilize duplex DNA

Fleming

Burrows

2017

Org. Biomol. Chem.

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In DNA, 2′-deoxyguanosine (dG) is susceptible to oxidative modification by reactive oxygen species (ROS) yielding many products, one of which is 8-oxo-7,8-dihydro-2′-deoxyguanosine (dOG). Interestingly, dOG is stable but much more labile toward oxidation than dG, furnishing 5-guanidinohydantoin-2′-deoxyribose (dGh) that is favored in the duplex context or spiroiminodihydantoin-2′-deoxyribose (dSp) that is favored in the oxidation of single-stranded contexts. Previously, exposure of DNA to ionizing radiation found ~50% of the dOG exists as a tandem lesion with an adjacent formamide site. The present work explored oxidation of dOG in a tandem lesion with a THF abasic site analog (F) that models the formamide on either the 5′ or 3′ side. When dOG was in a tandem lesion, both dGh and dSp were observed as oxidation products. The 5′ versus 3′ side in which F resided influenced the stereochemistry of the dSp formed. Further, tandem lesions with dOG were found to be up to two orders of magnitude more reactive to oxidation than dOG in an intact duplex. When dOG is in a tandem lesion it is up to fivefold more prone to formation of spermine cross-links during oxidation compared to dOG in an intact duplex. Lastly, dOG, dGh, and each dSp diastereomer were synthesized as part of a tandem lesion in a duplex DNA to establish that dOG tandem lesions decrease the thermal stability by 12–13 °C, while dGh or either dSp diastereomer in a tandem lesion decrease the stability by >20 °C. The biological consequences of these results are discussed.

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Repair of Hydantoin Lesions and Their Amine Adducts in DNA by Base and Nucleotide Excision Repair

Cited by 54 publications

References 95 publications

Base and Nucleotide Excision Repair of Oxidatively Generated Guanine Lesions in DNA

Base and Nucleotide Excision Repair of Oxidatively Generated Guanine Lesions in DNA

Reactivity of Damaged Pyrimidines: Formation of a Schiff Base Intermediate at the Glycosidic Bond of Saturated Dihydrouridine

8-Oxo-7,8-dihydro-2′-deoxyguanosine and abasic site tandem lesions are oxidation prone yielding hydantoin products that strongly destabilize duplex DNA

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