Formation of 13C-, 15N-, and 18O-Labeled Guanidinohydantoin from Guanosine Oxidation with Singlet Oxygen. Implications for Structure and Mechanism

Ye, Yu; Muller, James G.; Luo, Wenyi; Mayne, Charles L.; Shallop, Anthony J.; Jones, R. A. C.; Burrows, Cynthia J.

doi:10.1021/ja0378660

Cited by 169 publications

(277 citation statements)

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“…Further work is necessary to confirm the R and S designations of the monomer and oligomers. Of note, Gh also exists as a mixture of diastereomers, but these interconvert on a time scale that is too rapid to allow isolation and independent study (53).…”

Section: Discussionmentioning

confidence: 99%

Superior Removal of Hydantoin Lesions Relative to Other Oxidized Bases by the Human DNA Glycosylase hNEIL1

et al. 2008

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The DNA glycosylase hNEIL1 initiates the base excision repair (BER) of a diverse array of lesions, including ring-opened purines and saturated pyrimidines. Of these, the hydantoin lesions, guanidinohydantoin (Gh) and the two diastereomers of spiroiminodihydantoin (Sp1 and Sp2) have garnered much recent attention due to their unusual structures, high mutagenic potential and detection in cells. In order to provide insight into the role of repair, the excision efficiency by hNEIL1 of these hydantoin lesions relative to other known substrates was determined. Most notably, quantitative examination of the substrate specificity with hNEIL1 revealed that the hydantoin lesions are excised much more efficiently (> 100-fold faster) than the reported standard substrates thymine glycol (Tg) and 5-hydroxycytosine (5-OHC). Importantly, the glycosylase and β,δ-lyase reactions are tightly coupled such that the rate of the lyase activity does not influence the observed substrate specificity. The activity of hNEIL1 is also influenced by the base pair partner of the lesion, with both Gh and Sp removal being more efficient when paired with T, G or C than when paired with A. Notably, the most efficient removal is observed with the Gh or Sp paired in the unlikely physiological context with T; indeed, this may be a consequence of the unstable nature of base pairs with T. However, the facile removal via BER in promutagenic base pairs that are reasonably formed after replication (such as Gh:G) may be a factor that modulates the mutagenic profile of these lesions. In addition, hNEIL1 excises Sp1 faster than Sp2 indicating the enzyme can discriminate between the two diastereomers. This is the first time that a BER glycosylase has been shown to be able to preferentially excise one diastereomer of Sp. This may be a consequence of the architecture of the active site of hNEIL1 and the structural uniqueness of the Sp lesion. These results indicate that the hydantoin lesions are the best substrates identified thus far for hNEIL1, and suggest that repair of these lesions may be a critical function of the hNEIL1 enzyme in vivo.Cells experiencing oxidative stress have an overabundance of reactive oxygen species (ROS) such as superoxide, hydrogen peroxide, and hydroxyl radicals (1,2). ROS are present in cells as byproducts of endogenous metabolic reactions or as a result of external sources such as ionizing radiation. The reactions mediated by ROS can lead to various types of DNA damage including strand breaks, DNA-protein cross-links, abasic sites, and base lesions, which are potentially detrimental to cells (3)(4)(5)(6). Oxidative DNA damage is mitigated by a variety of DNA repair pathways (7-9). The importance of repairing DNA damage has been highlighted by the correlation between defects in DNA repair pathways and cancer (7,(10)(11)(12). ¶ This work was supported by a grant from the National Cancer Institute of the National Institutes of Health (CA90689). Although a variety of guanine oxidation products have been identified (13), most st...

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Section: Discussionmentioning

confidence: 99%

Superior Removal of Hydantoin Lesions Relative to Other Oxidized Bases by the Human DNA Glycosylase hNEIL1

et al. 2008

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“…19 Both Gh and Sp were formed via a 5-OH-8-oxoGua intermediate. 20 The use of the metalloporphyrin Mn-TMPyP/KHSO 5 leads to an oxidised Gh ox , not Gh, as the main oxidatively generated product of 75 Guanine oxidation, along with Iz and Oxa. 21 Peroxynitrite oxidation was also found to generate an oxidised form of Gh, oxidised Guanidinohydantoin (Gh ox ) in addition to both Gh and Sp.…”

Section: Introductionmentioning

confidence: 99%

Oxidised guanidinohydantoin (Gh^ox) and spiroiminodihydantoin (Sp) are major products of iron- and copper-mediated 8-oxo-7,8-dihydroguanine and 8-oxo-7,8-dihydro-2′-deoxyguanosine oxidation

et al. 2005

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8-Oxo-7,8-dihydroguanine (8-oxoGua), an important biomarker of DNA damage in oxidatively generated stress, is highly reactive towards further oxidation. Much work has been carried out to investigate the oxidation products of 8-oxoGua by one-electron oxidants, singlet oxygen, and peroxynitrite. This report details for the first time, the iron-and copper-mediated Fenton oxidation of 8-oxoGua and 8-oxo-7,8-dihydro-29-deoxyguanosine (8-oxodGuo). Oxidised guanidinohydantoin (Gh ox ) was detected as the major product of oxidation of 8-oxoGua with iron or copper and hydrogen peroxide, both at pH 7 and pH 11. Oxaluric acid was identified as a final product of 8-oxoGua oxidation. 8-oxodGuo was subjected to oxidation under the same conditions as 8-oxoGua. However, dGh ox was not generated. Instead, spiroiminodihydantoin (Sp) was detected as the major product for both iron and copper mediated oxidation at pH 7. It was proposed that the oxidation of 8-oxoGua was initiated by its one-electron oxidation by the metal species, which leads to the reactive intermediate 8-oxoGua ? + , which readily undergoes further oxidation. The product of 8-oxoGua and 8-oxodGuo oxidation was determined by the 29-deoxyribose moiety of the 8-oxodGuo, not whether copper or iron was the metal involved in the oxidation.

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“…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).…”

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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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Formation of ¹³C-, ¹⁵N-, and ¹⁸O-Labeled Guanidinohydantoin from Guanosine Oxidation with Singlet Oxygen. Implications for Structure and Mechanism

Cited by 169 publications

References 24 publications

Superior Removal of Hydantoin Lesions Relative to Other Oxidized Bases by the Human DNA Glycosylase hNEIL1

Superior Removal of Hydantoin Lesions Relative to Other Oxidized Bases by the Human DNA Glycosylase hNEIL1

Oxidised guanidinohydantoin (Gh^ox) and spiroiminodihydantoin (Sp) are major products of iron- and copper-mediated 8-oxo-7,8-dihydroguanine and 8-oxo-7,8-dihydro-2′-deoxyguanosine oxidation

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

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Formation of 13C-, 15N-, and 18O-Labeled Guanidinohydantoin from Guanosine Oxidation with Singlet Oxygen. Implications for Structure and Mechanism

Cited by 169 publications

References 24 publications

Superior Removal of Hydantoin Lesions Relative to Other Oxidized Bases by the Human DNA Glycosylase hNEIL1

Superior Removal of Hydantoin Lesions Relative to Other Oxidized Bases by the Human DNA Glycosylase hNEIL1

Oxidised guanidinohydantoin (Ghox) and spiroiminodihydantoin (Sp) are major products of iron- and copper-mediated 8-oxo-7,8-dihydroguanine and 8-oxo-7,8-dihydro-2′-deoxyguanosine oxidation

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

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Formation of ¹³C-, ¹⁵N-, and ¹⁸O-Labeled Guanidinohydantoin from Guanosine Oxidation with Singlet Oxygen. Implications for Structure and Mechanism

Oxidised guanidinohydantoin (Gh^ox) and spiroiminodihydantoin (Sp) are major products of iron- and copper-mediated 8-oxo-7,8-dihydroguanine and 8-oxo-7,8-dihydro-2′-deoxyguanosine oxidation