Photosensitized Oxidation of 5-Methyl-2‘-deoxycytidine by 2-Methyl-1,4-naphthoquinone:  Characterization of 5-(Hydroperoxymethyl)-2‘-deoxycytidine and Stable Methyl Group Oxidation Products

Bienvenu, Carine; Wagner, J. Richard; Cadet, Jean

doi:10.1021/ja962073h

Cited by 81 publications

(81 citation statements)

References 44 publications

(56 reference statements)

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“…2), 5-hydroxymethycytosine (5-HmCyt) and 5-formylcytosine (5-FoCyt), previously characterized in model studies involving oneelectron oxidant of the nucleoside (Bienvenu et al 1996), were found to be generated enzymatically and play a role in epigenetics (Kriaucionis and Heintz 2009;Tahiliani et al 2009;Iqbal et al 2011;Münzel et al 2011;Pfaffeneder et al 2011). More recently, 5-carboxycytosine (5-CaCyt) was characterized as the ultimate enzymatic oxidation product of 5-methylcytosine (Ito et al 2011;Pfaffeneder et al 2011;Wu and Zhang 2011;Zhang et al 2012).…”

Section: Enzymatic Oxidation Of 5-methylcytosine By Ten-eleven Translmentioning

confidence: 99%

DNA Base Damage by Reactive Oxygen Species, Oxidizing Agents, and UV Radiation

Cadet

Wagner

2013

Cold Spring Harbor Perspectives in Biology

629

461

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Emphasis has been placed in this article dedicated to DNA damage on recent aspects of the formation and measurement of oxidatively generated damage in cellular DNA in order to provide a comprehensive and updated survey. This includes single pyrimidine and purine base lesions, intrastrand cross-links, purine 5 0 ,8-cyclonucleosides, DNA-protein adducts and interstrand cross-links formed by the reactions of either the nucleobases or the 2-deoxyribose moiety with the hydroxyl radical, one-electron oxidants, singlet oxygen, and hypochlorous acid. In addition, recent information concerning the mechanisms of formation, individual measurement, and repair-rate assessment of bipyrimidine photoproducts in isolated cells and human skin upon exposure to UVB radiation, UVA photons, or solar simulated light is critically reviewed.I n this article, we emphasize recent developments in the formation of damage to cellular DNA mediated by reactive oxygen species (ROS) and oxidizing agents, including singlet oxygen, the hydroxyl radical ( † OH), one-electron oxidants, hypochlorous acid (HOCl), and ten-eleven translocation (TET) oxygenases involved in epigenetic regulation. These advances have been possible because of the development of sensitive and powerful high-performance liquid chromatography-mass spectrometry (HPLC-MS)/ mass spectrometry (MS) methods allowing one to revise previously reported data obtained using methods such as gas chromatographymass spectrometry (GC-MS), immunoassays, and HPLC with single MS detection (Cadet et al. , 2012a. Considerable progress has also been made in the elucidation of oxidative degradation pathways of isolated DNA and related model compounds (for recent comprehensive reviews, see Gimisis and Cismaş 2006;Neeley and Essigmann 2006;Pratviel and Meunier 2006;von Sonntag 2006;Cadet et al. 2008Cadet et al. , 2010Cadet et al. , 2012bDedon 2008;Burrows 2009;Wagner and Cadet 2010). In addition, there is much complementary information on solar-radiation-induced formation of bipyrimidine photoproducts in the DNA of fibroblasts, keratinocytes, and human skin. In particular, the distribution of UVA and UVB photoproducts has been determined, allowing accurate determination of their rates of repair (Cadet et al.

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Section: Enzymatic Oxidation Of 5-methylcytosine By Ten-eleven Translmentioning

confidence: 99%

DNA Base Damage by Reactive Oxygen Species, Oxidizing Agents, and UV Radiation

Cadet

Wagner

2013

Cold Spring Harbor Perspectives in Biology

629

461

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“…Hydroxyl radical-induced oxidation of DNA is complex, leading to a multitude of modifications at the level of DNA bases (thymine, cytosine, adenine, guanine, and 5-methylcytosine) and the sugar moiety (3,4). Using simple model systems, a large number of modified nucleosides has been identified (1)(2)(3)(4)(5)(6). H 2 O 2 -iron-mediated decomposition of 2Ј-deoxycytidine (dCyd) 1 was shown to lead to the formation of several stable products including oxidative modifications of the base and nucleoside in the product mixture (7).…”

mentioning

confidence: 99%

2′-Deoxycytidine Glycols, a Missing Link in the Free Radical-mediated Oxidation of DNA

Tremblay¹,

Douki²,

Cadet³

et al. 1999

Journal of Biological Chemistry

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2-Deoxycytidine glycols (5,6-dihydroxy-5,6-dihydro-2-deoxycytidine) are major products of the hydroxyl radical-induced oxidation of 2-deoxycytidine resulting from either a Fenton reaction or exposure to ionizing radiation. Because of their instability, however, the glycols have not previously been characterized. Instead, the impetus has been placed on the primary decomposition products of 2-deoxycytidine glycols, which includes 5-hydroxy-2-deoxycytidine, 5-hydroxy-2-deoxyuridine, and 2-deoxyuridine glycols. Here, we have identified one of the four possible diastereomers of 2-deoxycytidine glycols by product analyses of decomposition products, 1 H NMR, and mass spectrometry. This glycol was observed to decompose with a half-life of 50 min at 37°C in buffered neutral solutions and preferentially undergo dehydration to 5-hydroxy-2-deoxycytidine. The rate of decomposition was strongly dependent on pH (2-10) and the concentration of phosphate ion (10 -300 mM). Next, we report on the deamination of cytosine glycols to uracil glycols in oxidized DNA using acid hydrolysis and high performance liquid chromatography analysis with electrochemical detection to monitor 5-hydroxycytosine and 5-hydroxyuracil. The results showed that the lifetime of cytosine glycols is greatly enhanced in DNA (34-fold; half-life, 28 h), and that deamination accounts for at least one-third of the total decomposition. The relatively long lifetime of cytosine glycols in DNA suggests that this important class of DNA oxidation products will be significantly involved in repair and mutagenesis processes.The main species responsible for oxidative DNA damage in cells appear to be hydroxyl radicals that are generated by a Fenton reaction involving the reduction of H 2 O 2 by transition state metal ions (e.g. Fe 2ϩ or Cu ϩ ) (1). In addition, the indirect effects of ionizing radiation may be attributed predominantly to the reaction of hydroxyl radicals with DNA (2). Hydroxyl radical-induced oxidation of DNA is complex, leading to a multitude of modifications at the level of DNA bases (thymine, cytosine, adenine, guanine, and 5-methylcytosine) and the sugar moiety (3, 4). Using simple model systems, a large number of modified nucleosides has been identified (1-6). H 2 O 2 -iron-mediated decomposition of 2Ј-deoxycytidine (dCyd) 1 wasshown to lead to the formation of several stable products including oxidative modifications of the base and nucleoside in the product mixture (7). Recently, we identified 17 stable oxidative nucleoside modifications from ␥ irradiation and menadione photosensitization of dCyd in aerated aqueous solutions (8). The major products of these reactions included glycol, hydantoin, and formamide derivatives, with an intact sugar moiety, similar to the oxidation of 2Ј-deoxyuridine (dUrd) and thymidine. In addition, several unique products of dCyd were identified. Although dCyd glycols were not detected in the reaction mixture, the formation of these labile products is inferred by the presence of 5-hydroxy-2Ј-deoxycytidine (oh 5 dCyd) and ...

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“…Wichtig ist die Entdeckung, dass unter oxidativen Bedingungen neben hmC auch 5-Formyldesoxycytidin (fC oder dC oder 5fC) und 5-Carboxyldesoxycytidin (caC oder 5-COOH dC oder 5caC) gebildet werden. [11,12] Während fC über das Hydrat deformyliert werden kann, kann caC decarboxyliert werden, was zur Regeneration von Cytosin führt. Dies ist genau die Reaktivität, welche die derzeitige Spekulationen nährt, dass hmC ein Intermediat des gesuchten Reaktionspfads sein könnte, der die aktive Demethylierung ermöglicht.…”

Section: Methodsunclassified

“…In-vitro-Studien zeigten, dass Ein-Elektronen-Oxidation von mC in wässriger Lösung unter Sauerstoffeinfluss und UV-A-Bestrahlung zur Bildung von hmC führt. [11] Dies ist auch in der Anwesenheit des Typ-I-Photosensibilisators Menadion möglich, welcher die instabilen Peroxylradikal-oder Hydroxyperoxid-Intermediate erzeugt. Diese zerfallen zu hmC.…”

Section: Die Geschichte Von 5-hydroxymethylcytosinunclassified