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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Removal of oxygen free-radical-induced 5',8-purine cyclodeoxynucleosides from DNA by the nucleotide excision-repair pathway in human cells
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Removal of oxygen free-radical-induced 5',8-purine cyclodeoxynucleosides from DNA by the nucleotide excision-repair pathway in human cells

机译：通过人类细胞中的核苷酸切除修复途径从DNA上去除氧自由基诱导的5'，8-嘌呤环脱氧核苷

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摘要

Exposure of cellular DNA to reactive oxygen species generates several classes of base lesions many of which are removed by the base excision-repair pathway. However, the lesions include purine cyclodeoxynucleoside formation by intramolecular crosslinking between the C-8 position of adenine or guanine and the 5' position of 2-deoxyribose. This distorting form of DNA damage, in which the purine is attached by two covalent bonds to the sugar- phosphate backbone, occurs as distinct diastereoisomers. It was observed here that both diastereoisomers block primer extension by mammalian and microbial replicative DNA polymerases, using DNA with a site-specific purine cyclodeoxynucleoside residue as template, and consequently appear to be cytotoxic lesions. Plasmid DNA containing either the 5'R or 5'S form of 5',8-cyclo-2-deoxya- denosine was a substrate for the human nucleotide excision-repair enzyme complex. The R diastereoisomer was more efficiently repaired than the S isomer. No correction of the lesion by direct damage reversal or base excision repair was detected. Dual incision around the lesion depended on the core nucleotide excision-repair protein XPA. In contrast to several other types of oxidative DNA damage, purine cyclodeoxynucleosides are chemically stable and would be expected to accumulate at a slow rate over many years in the DNA of nonregenerating cells from xeroderma pigmentosum patients. High levels of this form of DNA damage might explain the progressive neurodegeneration seen in XPA individuals.
机译：细胞DNA暴露于活性氧会产生几类基础病变，其中许多通过基础切除修复途径被清除。然而，损伤包括腺嘌呤或鸟嘌呤的C-8位与2-脱氧核糖的5'位之间的分子内交联形成的嘌呤环脱氧核苷。 DNA破坏的这种扭曲形式是嘌呤通过两个共价键连接到糖磷酸骨架上，并以不同的非对映异构体形式出现。在此观察到，两种非对映异构体均以具有位点特异性嘌呤环脱氧核苷残基的DNA为模板，通过哺乳动物和微生物复制性DNA聚合酶阻断引物延伸，因此似乎是细胞毒性损伤。含有5'，8-环-2-脱氧腺苷的5'R或5'S形式的质粒DNA是人核苷酸切除修复酶复合物的底物。 R非对映异构体比S异构体更有效地被修复。未检测到直接损伤逆转或基础切除修复对病变的矫正。病变周围的双重切口取决于核心核苷酸切除修复蛋白XPA。与其他几种类型的氧化性DNA损伤相反，嘌呤环脱氧核苷在化学上是稳定的，并且有望在许多年内以缓慢的速度从色素干性皮肤病患者的非再生细胞DNA中积累。这种高水平的DNA损伤可能解释了XPA个体中进行性神经退行性变。

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