7,8-Dihydro-8-oxo-2‘-deoxyguanosine Residues in DNA Are Radiation Damage “Hot” Spots in the Direct γ Radiation Damage Pathway

Doddridge, Zara A.; Cullis, Paul M.; Jones, George D.D.; Malone, Mark E.

doi:10.1021/ja9816234

Cited by 42 publications

(34 citation statements)

References 20 publications

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“…It has a lower oxidation potential than any of the unmodified DNA bases, including Guanine itself, 8 and has been identified as a "hotspot" for oneelectron and singlet oxygen oxidation. 9 The exact nature of Guanine, and indeed 8-oxoGua, oxidation appears to depend 45 on the nature of the nucleobase reactant (e.g., dG, singestranded oligomer, double-stranded oligomer) and reaction conditions (pH, temperature), as well as the nature of the oxidant. Table 1 summarises published work on the oxidation products of 8-oxodGuo.…”

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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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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“…This high background of strand breaks complicates analysis of the sequence selectivity of base oxidation and necessitates the use of indirect approaches in studies of charge transfer with ionizing radiation, such as the use of easily ionized base analogs. For example, Doddridge et al (26) demonstrated that 7,8-dihydro-8-oxoguanine (8-oxo-G), with its lower reduction potential than G (0.74 V versus NHE; see Ref. 25), served as a damage hot spot when placed in an oligodeoxynucleotide that was subjected to ␥-irradiation under dry film conditions that obviate the indirect effects.…”

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confidence: 99%

DNA Sequence Context as a Determinant of the Quantity and Chemistry of Guanine Oxidation Produced by Hydroxyl Radicals and One-electron Oxidants

Margolin

Shafirovich

Geacintov

et al. 2008

Journal of Biological Chemistry

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DNA sequence context has emerged as a critical determinant of the location and quantity of nucleobase damage caused by many oxidizing agents. However, the complexity of nucleobase and 2-deoxyribose damage caused by strong oxidants such as ionizing radiation and the Fenton chemistry of Fe 2؉ -EDTA/ H 2 O 2 poses a challenge to defining the location of nucleobase damage and the effects of sequence context on damage chemistry in DNA. To address this problem, we developed a gel-based method that allows quantification of nucleobase damage in oxidized DNA by exploiting Escherichia coli exonuclease III to remove fragments containing direct strand breaks and abasic sites. The rigor of the method was verified in studies of guanine oxidation by photooxidized riboflavin and nitrosoperoxycarbonate, for which different effects of sequence context have been demonstrated by other approaches (Margolin, Y., Cloutier, J. F., Shafirovich, V., Geacintov, N. E., and Dedon, P. C. (2006) Nat. Chem. Biol. 2, 365-366). Using duplex oligodeoxynucleotides containing all possible three-nucleotide sequence contexts for guanine, the method was used to assess the role of DNA sequence context in hydroxyl radical-induced guanine oxidation associated with ␥-radiation and Fe 2؉ -EDTA/H 2 O 2 . The results revealed both differences and similarities for G oxidation by hydroxyl radicals and by one-electron oxidation by riboflavin-mediated photooxidation, which is consistent with the predominance of oxidation pathways for hydroxyl radicals other than one-electron oxidation to form guanine radical cations. Although the relative quantities of G oxidation produced by hydroxyl radicals were more weakly correlated with sequencespecific ionization potential than G oxidation produced by riboflavin, damage produced by both hydroxyl radical generators and riboflavin within two-and three-base runs of G showed biases in location that are consistent with a role for electron transfer in defining the location of the damage products. Furthermore, both ␥-radiation and Fe 2؉ -EDTA/H 2 O 2 showed relatively modest effects of sequence context on the proportions of different damage products sensitive to E. coli formamidopyrimidine DNA glycosylase and hot piperidine, although GT-containing sequence contexts displayed subtle biases in damage chemistry (formamidopyrimidine DNA glycosylase/piperidine ratio). Overall, the results are consistent with the known chemistry of guanine oxidation by hydroxyl radical and demonstrate that charge migration plays a relatively minor role in determining the location and chemistry of hydroxyl radical-mediated oxidative damage to guanine in DNA.With implications for mutagenesis and carcinogenesis, DNA damage caused by strong oxidizing agents such as ionizing radiation and Fenton chemistry (e.g. Fe 2ϩ -EDTA, Cu ϩ /H 2 O 2 ) affects both the base and sugar moieties (1, 2). This complexity poses a challenge to understanding the mechanisms of formation of the ultimate stable oxidation products and their relative amounts, especially in terms of...

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“…An important and increasingly recognized feature of OG is that it is highly reactive toward further oxidation, with several in vitro studies illustrating that OG is a "hot spot" for oxidative damage (26)(27)(28)(29)(30). Indeed, redox potentials for an OG nucleoside have been reported to be between 0.58 and 0.75 V versus the normal hydrogen electrode (NHE), significantly lower than that of the 2′-deoxyguanosine nucleoside (1.29 V vs NHE) (26,31,32).…”

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Removal of Hydantoin Products of 8-Oxoguanine Oxidation by the Escherichia coli DNA Repair Enzyme, FPG

et al. 2000

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An intriguing feature of 7,8-dihydro-8-oxo-2'-deoxyguanosine (OG) is that it is highly reactive toward further oxidation. Indeed, OG has been shown to be a "hot spot" for oxidative damage and susceptible to oxidation by a variety of cellular oxidants. Recent work has identified two new DNA lesions, guanidinohydantoin (Gh) and spiroiminodihydantoin (Sp), resulting from one-electron oxidation of OG. The presence of Gh and Sp lesions in DNA templates has been shown to result in misinsertion of G and A by DNA polymerases, and therefore, both are potentially mutagenic DNA lesions. The base excision repair (BER) glycosylases Fpg and MutY serve to prevent mutations associated with OG in Escherichia coli, and therefore, we have investigated the ability of these two enzymes to process DNA duplex substrates containing the further oxidized OG lesions, Gh and Sp. The Fpg protein, which removes OG and a variety of other oxidized purine base lesions, was found to remove Gh and Sp efficiently opposite all four of the natural DNA bases. The intrinsic rate of damaged base excision by Fpg was measured under single-turnover conditions and was found to be highly dependent upon the identity of the base opposite the OG, Gh, or Sp lesion; as expected, OG is removed more readily from an OG:C- than an OG:A-containing substrate. However, when adenine is paired with Gh or Sp, the rate of removal of these damaged lesions by Fpg was significantly increased relative to the rate of removal of OG from an OG:A mismatch. The adenine glycosylase MutY, which removes misincorporated A residues from OG:A mismatches, is unable to remove A paired with Gh or Sp. Thus, the activity of Fpg on Gh and Sp lesions may dramatically influence their mutagenic potential. This work suggests that, in addition to OG, oxidative products resulting from further oxidation of OG should be considered when evaluating oxidative DNA damage and its associated effects on DNA mutagenesis.

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7,8-Dihydro-8-oxo-2‘-deoxyguanosine Residues in DNA Are Radiation Damage “Hot” Spots in the Direct γ Radiation Damage Pathway

Cited by 42 publications

References 20 publications

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

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

DNA Sequence Context as a Determinant of the Quantity and Chemistry of Guanine Oxidation Produced by Hydroxyl Radicals and One-electron Oxidants

Removal of Hydantoin Products of 8-Oxoguanine Oxidation by the Escherichia coli DNA Repair Enzyme, FPG

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7,8-Dihydro-8-oxo-2‘-deoxyguanosine Residues in DNA Are Radiation Damage “Hot” Spots in the Direct γ Radiation Damage Pathway

Cited by 42 publications

References 20 publications

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

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

DNA Sequence Context as a Determinant of the Quantity and Chemistry of Guanine Oxidation Produced by Hydroxyl Radicals and One-electron Oxidants

Removal of Hydantoin Products of 8-Oxoguanine Oxidation by the Escherichia coli DNA Repair Enzyme, FPG

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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

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