Tandem Lesions Arising from 5-(Uracilyl)methyl Peroxyl Radical Addition to Guanine: Product Analysis and Mechanistic Studies.,Chemical Research in Toxicology

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Tandem Lesions Arising from 5-(Uracilyl)methyl Peroxyl Radical Addition to Guanine: Product Analysis and Mechanistic Studies.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2019-12-27 , DOI: 10.1021/acs.chemrestox.9b00407
Gabriel Robert ₁ , J Richard Wagner _{1,

2}

Affiliation

The reaction of hydroxyl radical (HO•) with thymine in DNA generates 5-(uracilyl)-methyl radicals (T•) and the corresponding methylperoxyl radical (TOO•) in the presence of O2, which in turn propagates damage by reacting with a vicinal nucleobase. This leads to so-called double or tandem lesions. Because methyl oxidation products of thymine are major products, we investigated the reactivity of TOO• using a photolabile precursor: 5-(phenylthiomethyl)uracil (TSPh). The precursor was prepared and incorporated into a DNA trinucleotide: 5'-d(GpTSPhpA)-3' (G-TSPh-A). Upon photolysis, the resulting products were characterized by LC-MS/MS. Thereby, we identified four tandem lesions involving GpT, which include either 2,6-diamino-4-hydroxy-5-formamidopyrimidine (fapyG) or 8-oxo-7,8-dihydroguanine (oxoG) in tandem with either 5-formyluracil (fU) or 5-hydroxymethyluracil (hmU). The formation of these tandem lesions is explained by initial addition of TOO• to the C8 of guanine moiety, giving an N7-guanine cross-linked radical. The latter radical undergoes either reduction to an 7,8-saturated endoperoxide or oxidation to an 7,8-unsaturated endoperoxide, which transform into fapyG-fU-A and oxoG-fU-A, respectively. This is supported by the effect of a reducing (dithiothreitol) and oxidizing agent (Fe3+) on product formation. This study expands the repertoire of tandem lesions that can occur at GpT sequences and underlines the importance of redox environment.

中文翻译：

5-（尿嘧啶基）甲基过氧自由基向鸟嘌呤加成引起的串联病变：产物分析和机理研究。

氧自由基（HO•）与胸腺嘧啶在DNA中的反应在O2存在下产生5-（尿嘧啶）-甲基自由基（T•）和相应的甲基过氧自由基（TOO•），而后者又通过与A2反应而传播破坏。邻近核碱基。这导致所谓的双重或串联损伤。由于胸腺嘧啶的甲基氧化产物是主要产物，因此我们使用光不稳定的前体：5-（苯硫基甲基）尿嘧啶（TSPh）研究了TOO•的反应性。制备前体并掺入DNA三核苷酸：5'-d（GpTSPhpA）-3'（G-TSPh-A）。光解后，通过LC-MS / MS对所得产物进行表征。因此，我们确定了4个涉及GpT的串联损伤，包括2,6-二氨基-4-羟基-5-甲酰胺基嘧啶（fapyG）或8-oxo-7，与5-甲酰尿嘧啶（fU）或5-羟甲基尿嘧啶（hmU）串联使用的8-二氢鸟嘌呤（oxoG）。这些串联损伤的形成可以通过向鸟嘌呤部分的C8初始添加TOO•来解释，从而得到N7-鸟嘌呤交联的基团。后者自由基经历还原成7,8-饱和内过氧化物或氧化成7,8-不饱和内过氧化物，其分别转化为fapyG-fU-A和oxoG-fU-A。还原剂（二硫苏糖醇）和氧化剂（Fe3 +）对产物形成的影响支持了这一点。这项研究扩大了可能在GpT序列上发生的串联损伤的范围，并强调了氧化还原环境的重要性。给出一个N7-鸟嘌呤交联的基团后者自由基经历还原成7,8-饱和内过氧化物或氧化成7,8-不饱和内过氧化物，其分别转化为fapyG-fU-A和oxoG-fU-A。还原剂（二硫苏糖醇）和氧化剂（Fe3 +）对产物形成的影响支持了这一点。这项研究扩大了可能在GpT序列上发生的串联损伤的范围，并强调了氧化还原环境的重要性。给出一个N7-鸟嘌呤交联的基团后者自由基经历还原成7,8-饱和内过氧化物或氧化成7,8-不饱和内过氧化物，其分别转化为fapyG-fU-A和oxoG-fU-A。还原剂（二硫苏糖醇）和氧化剂（Fe3 +）对产物形成的影响支持了这一点。这项研究扩大了可能在GpT序列上发生的串联损伤的范围，并强调了氧化还原环境的重要性。

更新日期：2019-12-27

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