Structural and Thermodynamic Features of Spiroiminodihydantoin Damaged DNA Duplexes

Jia, Lei; Shafirovich, Vladimir; Shapiro, Robert; Geacintov, Nicholas E.; Broyde, Suse

doi:10.1021/bi050790v

Cited by 49 publications

(108 citation statements)

References 90 publications

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“…It may be added that recent quantum mechanic geometry optimization calculations indicated that among the three possible tautomers for the hydantoin ring B of the base, the amino form exhibits the lowest energy (30,31). Interestingly, dipolar interactions were observed between the NH-3 proton on one hand and H-2′ and H-2′′ on the other hand for nucleoside 1.…”

Section: Table 2 Coupling Constants (J/hz) For Diastereomers 1 (S) Amentioning

confidence: 99%

Nuclear Magnetic Resonance Studies of the 4R and 4S Diastereomers of Spiroiminodihydantoin 2‘-Deoxyribonucleosides: Absolute Configuration and Conformational Features

Karwowski

Dupeyrat

Bardet

et al. 2006

Chem. Res. Toxicol.

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The present study was aimed at gaining further insights into stereochemical and conformational features of the 4R and 4S diastereomers of spiroiminodihydantoin 2'-deoxyribonucleosides that have been shown to be the predominant singlet oxygen oxidation products of 2'-deoxyguanosine in aqueous solutions. It may be added that spiroiminodihydantoin derivatives are efficiently generated by one-electron and singlet oxygen oxidation of the 8-oxo-7,8-dihydroguanine moiety of several nucleic acid components including nucleosides, nucleotides, and oligonucleotides. The reported structural data on the pair of diastereomeric spiroiminodihydantoin 2'-deoxyribonucleosides 1 and 2 are mostly inferred from extensive (1)H and (13)C NMR analyses including two-dimensional nuclear Overhauser effect measurements performed in both D(2)O and dimethyl sulfoxide. This approach that has been shown previously to be suitable to assign the stereochemistry of the base moiety of oxidized pyrimidine nucleosides was completed by molecular modeling and quantum mechanics studies. Thus, application of these two complementary approaches together with the consideration of the results of a recent relevant quantum mechanic study has allowed the assignment of the absolute stereoconfiguration of the C-4 carbon of diastereomers 1 and 2. In addition, information is provided on the conformational features of the 2-deoxyribose moiety and the orientation of the base around the N-glycosidic bond of both 2'-deoxyribonucleosides 1 and 2.

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Section: Table 2 Coupling Constants (J/hz) For Diastereomers 1 (S) Amentioning

confidence: 99%

Nuclear Magnetic Resonance Studies of the 4R and 4S Diastereomers of Spiroiminodihydantoin 2‘-Deoxyribonucleosides: Absolute Configuration and Conformational Features

Karwowski

Dupeyrat

Bardet

et al. 2006

Chem. Res. Toxicol.

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“…On the other hand, the stereoisomeric Sp structures exist as stable and identifiable R and S stereoisomers (24,83). 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.…”

Section: Reaction1mentioning

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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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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“…Earlier computational work had predicted a better hydrogen bonding network with R-Sp than with the S stereoisomer, suggesting that R-Sp might display a greater stability in our DSC studies. 25 We did not find this to be the case, and in fact, Khutsishvili et al . recently found a similar result with 11-mer duplexes containing the Sp lesion.…”

Section: Resultsmentioning

confidence: 59%

Effect of Base-Pairing Partner on the Thermodynamic Stability of the Diastereomeric Spiroiminodihydantoin Lesion

Gruessner

Dwarakanath

Stewart

et al. 2016

Chem. Res. Toxicol.

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Oxidation of guanine by reactive oxygen species and high valent metals produces damaging DNA base lesions like 8-oxo-7,8-dihydroguanine (8-oxoG). 8-oxoG can be further oxidized to form the spiroiminodihydantoin (Sp) lesion, which is even more mutagenic. DNA polymerases preferentially incorporate purines opposite the Sp lesion, and DNA glycosylases excise the Sp lesion from the duplex, although the rate of repair is different for the two Sp diastereomers. To further understand the biological processing of the Sp lesion, differential scanning calorimetry (DSC) studies were performed on a series of 15-mer DNA duplexes. The thermal and thermodynamic stability of each of the Sp diastereomers paired to the four standard DNA bases was investigated. It was found that, regardless of the base-pairing partner, the Sp lesion was always highly destabilizing in terms of DNA melting temperature, enthalpic stability, and overall duplex free energy. We found no significant differences between the two Sp diastereomers, but changing the base pairing partner of the Sp lesion produced slight differences in stability. Specifically, duplexes with Sp:C pairings were always the most destabilized, whereas pairing the Sp lesion with a purine base modestly increased stability. Overall, these results suggest that although the stability of the Sp diastereomers cannot explain the differences in the rates of repair by DNA glycosylases, the most stable base pairing partners do correspond with the nucleotide preference of DNA polymerases.

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Structural and Thermodynamic Features of Spiroiminodihydantoin Damaged DNA Duplexes

Cited by 49 publications

References 90 publications

Nuclear Magnetic Resonance Studies of the 4R and 4S Diastereomers of Spiroiminodihydantoin 2‘-Deoxyribonucleosides: Absolute Configuration and Conformational Features

Nuclear Magnetic Resonance Studies of the 4R and 4S Diastereomers of Spiroiminodihydantoin 2‘-Deoxyribonucleosides: Absolute Configuration and Conformational Features

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

Effect of Base-Pairing Partner on the Thermodynamic Stability of the Diastereomeric Spiroiminodihydantoin Lesion

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