Peroxyl radical mediated oxidative DNA base damage: implications for lipid peroxidation induced mutagenesis.
Peroxyl radical mediated oxidative DNA base damage: implications for lipid peroxidation induced mutagenesis.
复制标题
过氧自由基介导的氧化 DNA 碱基损伤：对脂质过氧化诱导突变的影响。
DOI：
10.1021/bi048276x
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Termini,John
中科院分区：
文献类型：
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作者：
Lim,Punnajit;Wuenschell,GeraldE;Holland,Vanessa;Lee,Dong-Hyun;Pfeifer,GerdP;Rodriguez,Henry;Termini,John
脂质过氧化引起的内源性DNA损伤被认为在致癌过程中起关键作用。脂质过氧化产生自由基中间体（主要是过氧自由基，ROO•）和亲电醛作为主要的基因毒物。虽然关于醛基加合物在突变和致癌中的作用的详细信息是可用的，但对过氧自由基介导的DNA碱基损伤的贡献知之甚少。在目前的研究中，我们绘制了由过氧自由基诱导的氧化碱基损伤在upftrna基因，并将这一信息与过氧化诱导的突变在几个人类成纤维细胞系。脱氧核糖核酸（DNA）与过氧化物花生四烯酸（20:4ω6）或氧存在下由ABIP热裂解产生的过氧自由基反应均可获得几乎相同的氧化碱基损伤模式。氧化碱基损伤主要发生在G和c位点。在所有细胞系中均检测到该基因GC碱基对的翻转。还观察到过氧自由基诱导的串联突变。许多突变热点与绘制的氧化损伤位点一致，尽管在某些情况下热点发生在受损碱基附近。证据提出了8-oxodG参与氧化DNA的ROO•。这些结果用于解释先前发表的由人类细胞脂质过氧化诱导的突变谱的一些关键特征。
Endogenous DNA damage induced by lipid peroxidation is believed to play a critical role in carcinogenesis. Lipid peroxidation generates free radical intermediates (primarily peroxyl radicals, ROO•) and electrophilic aldehydes as the principal genotoxicants. Although detailed information is available on the role of aldehyde base adducts in mutagenesis and carcinogenesis, the contribution of peroxyl radical mediated DNA base damage is less well understood. In the present study we have mapped oxidative base damage induced by peroxyl radicals in thesupFtRNA gene and correlated this information with peroxidation-induced mutations in several human fibroblast cell lines. Nearly identical patterns of oxidative base damage were obtained from reaction of DNA with either peroxidizing arachidonic acid (20:4ω6) or peroxyl radicals generated by thermolysis of ABIP in the presence of oxygen. Oxidative base damage primarily occurred at G and C. Transversions at GC base pairs in thesupFgene were the major base substitution detected in all cell lines. Peroxyl radical induced tandem mutations were also observed. Many mutation hot spots coincided with sites of mapped oxidative lesions, although in some cases hot spots occurred adjacent to the damaged base. Evidence is presented for the involvement of 8-oxodG in the oxidation of DNA by ROO•. These results are used to interpret some key features of previously published mutation spectra induced by lipid peroxidation in human cells.