Peroxynitrite reaction products of 3′,5′-di
            <i>-O-</i>
            acetyl-8-oxo-7,8-dihydro-2′-deoxyguanosine

Niles, Jacquin C.; Burney, Samar; Singh, Sachin; Wishnok, John S.; Tannenbaum, Steven R.

doi:10.1073/pnas.96.21.11729

Cited by 82 publications

(87 citation statements)

References 43 publications

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“…When exposed to a large dose of peroxynitrite delivered to the system instantaneously, the 8-oxoGua nucleoside was converted primarily to DGh, NO 2 -DGh, and CAC (Chart 1) (23). Furthermore, DGh and NO 2 -DGh are hydrolytically unstable and can decompose to Oa and subsequently to Ur (23). In contrast, when peroxynitrite was delivered at a lower flux using SIN-1, the two Sp diasteromers, Gh, and HICA predominated (26,27).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, although 8-oxoGua does not readily depurinate, this lesion is chemically labile toward further oxidation and/or nitration, and several secondary lesions have been identified (Chart 1) (14,15). These include guanidinohydantoin (Gh) and its isomer iminoallantoin (Ia) (16), the two diastereomers of spiroiminodihydantoin (Sp) (17,18), oxaluric acid (Oa) (19,20), urea (Ur) (21), N-nitrodehydroguanidinohydantoin (NO 2 -DGh) (22), dehydroguanidinohydantoin (DGh) (23,24), 2,4,6-trioxo [1,3,5]triazinane-1-carboxamidine (CAC) (25), 4-hydroxy-2,5-dioxoimidazolidine-4-carboxylic acid (HICA) (26,27), cyanuric acid (Ca) (25,28), oxazolone (Oz) (29), imidazolone (Iz) (23), and 2-amino-4-hydroxy-s-triazine-6-carboxylic acid (triazine) (30,31).…”

Section: Introductionmentioning

confidence: 99%

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Chemical–Biological Fingerprinting: Probing the Properties of DNA Lesions Formed by Peroxynitrite

Delaney

Essigmann

2007

Chem. Res. Toxicol.

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DNA-damaging agents usually produce a vast collection of lesions within the genome. Analysis of these lesions from the structural and biological viewpoints is often complicated by the reality that some of the lesions are chemically fragile, leading to an even larger set of secondary and tertiary products. In an effort to deconvolute complex DNA-damage spectra, a strategy is presented whereby an oligonucleotide containing a specific target for chemical reaction is allowed to react with a DNAdamaging agent. A large collection of HPLC-resolvable modified oligonucleotides is generated, and chromatographically distinct members of the set are then individually characterized using chemical, spectroscopic, biochemical, and genetic probes. The biological component of this "chemicalbiological fingerprinting" tool is the use of polymerase bypass in vivo in cells having defined replication status and quantitative and qualitative patterns of lesion-directed mutagenesis, as key properties that complement physical analysis of modified DNA. This approach was applied to the complex product spectrum generated by peroxynitrite in the presence of CO 2 ; peroxynitrite is a powerful oxidizing and nitrating agent generated as part of immune response. An oligonucleotide containing the primary oxidation product, 7,8-dihydro-8-oxoguanine (8-oxoGua), which is highly susceptible to further oxidation and/or nitration, was treated with peroxynitrite. Using mass spectrometry, coelution with authentic standards, sensitivity to piperidine, recognition and strand cleavage by the DNA repair enzyme MutM, and mutagenicity and genotoxicity in vivo, a matrix was created that defined the properties of the secondary DNA lesions formed when 3-morpholinosydnonimine (SIN-1) delivered a low, constant flux of peroxynitrite to an oligonucleotide containing 8-oxoGua. Two lesions were identified as the diastereomers of spiroiminodihydantoin (Sp), which had been observed previously in nucleoside-based experiments employing SIN-1. A third lesion, triazine, was tentatively identified. However, in addition to these lesions, a number of secondary lesions were generated that had chemical-biological fingerprints inconsistent with that of any known 8-oxoGua-derived lesion described to date. In vitro experiments showed that while some of these newly characterized secondary lesions were removed from DNA by MutM, others were in fact very poor substrates for this repair enzyme. These 8-oxoGua-derived lesions also showed varying degrees of sensitivity to piperidine. Furthermore, all of the secondary lesions observed in this work were potently mutagenic and genotoxic in Escherichia coli. Therefore, while 8-oxoGua itself is nontoxic and only mildly mutagenic in repair-proficient cells, peroxynitrite reveals the promutagenic potential and triggers the covert nature of this DNA lesion. Supporting Information Available: HPLC chromatogram for the reaction between the 8-oxoGua oligonucleotide and SIN-1 (33.3-fold excess of SIN-1), PAGE results following piperidine and Mut...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chemical–Biological Fingerprinting: Probing the Properties of DNA Lesions Formed by Peroxynitrite

Delaney

Essigmann

2007

Chem. Res. Toxicol.

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“…15). Interpretation of analyses of 8-oxo-Guo formed by the human myeloperoxidase system and activated neutrophils is complicated because 8-oxo-Guo, once formed, can be also easily converted to further oxidation products by oxidants (35). We have recently identified diastereomers of spiroiminodihydantoin nucleoside as an oxidized product formed by reaction of 8-oxodGuo with HOCl or with a myeloperoxidase-H 2 O 2 -Cl Ϫ system (36).…”

Section: Table I Effect Of Ferrous and Ferric Ions On Hocl-mediated Fmentioning

confidence: 99%

Chlorination of Guanosine and Other Nucleosides by Hypochlorous Acid and Myeloperoxidase of Activated Human Neutrophils

Masuda¹,

Suzuki²,

Friesen³

et al. 2001

Journal of Biological Chemistry

133

119

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Activated human neutrophils secrete myeloperoxidase, which generates HOCl from H 2 O 2 and Cl ؊ . We have found that various (2-deoxy)nucleosides react with HOCl to form chlorinated (2-deoxy)nucleosides, including novel 8-chloro(2-deoxy)guanosine, 5-chloro(2-deoxy)cytidine, and 8-chloro(2-deoxy)adenosine formed in yields of 1.6, 1.6, and 0.2%, respectively, when 0.5 mM nucleoside reacted with 0.5 mM HOCl at pH 7.4. The relative chlorination, oxidation, and nitration activities of HOCl, myeloperoxidase, and activated human neutrophils in the presence and absence of nitrite were studied by analyzing 8-chloro-, 8-oxo-7,8-dihydro-, and 8-nitroguanosine, respectively, using guanosine as a probe. 8-Chloroguanosine was always more easily formed than 8-oxo-7,8-dihydro-or 8-nitro-guanosine. Using electrospray ionization tandem mass spectrometry, we show that several chlorinated nucleosides including 8-chloro(2-deoxy)guanosine are formed following exposure of isolated DNA or RNA to HOCl. Micromolar concentrations of tertiary amines such as nicotine and trimethylamine dramatically enhanced chlorination of free (2-deoxy)nucleosides and nucleosides in RNA by HOCl. As the G؊463A polymorphism of the MPO gene, which strongly reduces myeloproxidase mRNA expression, is associated with a reduced risk of lung cancer, chlorination damage of DNA /RNA and nucleosides by myeloperoxidase and its enhancement by nicotine may be important in the pathophysiology of human diseases associated with tobacco habits.

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“…However, a wide variety of oxidized guanine lesions have been identified, either resulting from further oxidation of OG or from direct oxidation of G (16). Of these further oxidized products, the hydantoin lesions, spiroiminodihydantoin (Sp) and guanidinohydantoin (Gh) (17,18) ( Figure 1A) have interesting structural properties, and have been identified as products in isolated DNA from oxidation of G and OG with a variety of oxidants, including singlet oxygen (19,20), type I photochemistry involving superoxide (21,22), high-valent chromium compounds (23,24) and peroxynitrite (25)(26)(27). The ability to form Sp and Gh under a variety of conditions is highly suggestive of their formation within cells.…”

Section: Introductionmentioning

confidence: 99%

Unusual Structural Features of Hydantoin Lesions Translate into Efficient Recognition by Escherichia coli Fpg

et al. 2007

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Oxidation of guanine (G) and 8-oxoguanine (OG) with a wide variety of oxidants yields the hydantoin lesions, guanidinohydantoin (Gh) and spiroiminodihydantoin (Sp). These two lesions have garnered much recent attention due to their unusual structures and high mutagenic potential. We have previously shown that duplexes containing Gh and Sp are substrates for the base excision repair glycosylase Escherichia coli Fpg (EcFpg). In order to evaluate the recognition features of these unusual lesions, binding and footprinting experiments were performed using a glycosylase inactive variant, E3Q EcFpg and 30 bp duplexes containing the embedded lesions. Surprisingly, E3Q EcFpg was found to bind significantly more tightly (~1000-fold) to duplexes containing Gh or Sp over the corresponding duplexes containing OG. This may be a consequence of the helixdestabilizing nature of the hydantoin lesions that facilitates their recognition within duplex DNA. Though DNA binding affinities of E3Q EcFpg with Gh-and Sp-containing duplexes were found to be similar to each other, hydroxyl radical footprinting using methidium-propyl-EDTA (MPE)-Fe(II) revealed subtle differences between binding of E3Q EcFpg with the two lesions. Most notably, in the presence of E3Q EcFpg, the Sp nucleotide (nt) is hyperreactive towards cleavage by MPE-Fe(II) generated hydroxyl radicals suggestive of the formation of an intercalation site for the MPE-Fe(II) reagent at the Sp nt. Interestingly, increasing the duplex length from 18 to 30 bp enhanced the excision efficiency of Gh and Sp paired with C, G or T by EcFpg such that these substrates are processed as efficiently as the signature substrate lesion OG. Moreover, the base removal activity with these two lesions was more efficient than removal of OG when in a base pairing context opposite A. The high affinity and efficient activity of EcFpg towards the hydantoin lesions suggests that EcFpg mediates repair of the lesions in vivo. Notably, the facile activity of EcFpg towards Gh and Sp in base pairing contexts with G and A, which are likely to be present after DNA replication, would be detrimental and enhance mutagenesis.Reactive oxygen species (ROS), 1 such as superoxide, hydrogen peroxide, and hydroxyl radicals, are formed as byproducts of cellular metabolism or indirectly via external sources such as ionizing radiation (1,2). The presence of ROS can lead to various types of DNA damage † This work was supported by a grant from the National Cancer Institute of the National Institutes of Health (CA90689) *Corresponding Author: SSD: telephone: (530)-752-4830; fax: (530)-752-8995, Email address: david@chem.ucdavis.edu. + Department of Chemistry, University of California, Davis ℵ Department of Chemistry, University of Utah 2 Most glycosylases have a high affinity for the product, and in many cases higher than for the substrate. It should also be noted that many of the previous reports measured the K d values using DNA concentrations that were close to K d (i.e. too high), and this may also contribute to i...

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Peroxynitrite reaction products of 3′,5′-di -O- acetyl-8-oxo-7,8-dihydro-2′-deoxyguanosine

Cited by 82 publications

References 43 publications

Chemical–Biological Fingerprinting: Probing the Properties of DNA Lesions Formed by Peroxynitrite

Chemical–Biological Fingerprinting: Probing the Properties of DNA Lesions Formed by Peroxynitrite

Chlorination of Guanosine and Other Nucleosides by Hypochlorous Acid and Myeloperoxidase of Activated Human Neutrophils

Unusual Structural Features of Hydantoin Lesions Translate into Efficient Recognition by Escherichia coli Fpg

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