期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：12
页码：5528-5533
DOI：10.1073/pnas.1000193107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Reaction of HO[bullet] radicals with double-stranded calf thymus DNA produces high levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and, to a minor extent, 8-oxo-7,8-dihydro-2'-deoxyadenosine (8-oxodAdo). Formation of the hydroxylated purine lesions is explained by addition of HO[bullet] to the C8 position of the purine moiety. It has been reported that tandem lesions containing a formylamine residue neighboring 8-oxodGuo could be produced through addition of a transiently generated pyrimidine peroxyl radical onto the C8 of an adjacent purine base. Formation of such tandem lesions accounted for {approx}10% of the total 8-oxodGuo. In the present work we show that addition of HO[bullet] onto the C8 of purine accounts for only [~]5% of the generated 8-oxodGuo. About 50% of the 8-hydroxylated purine lesions, including 8-oxodGuo and 8-oxodAdo, are involved in tandem damage and are produced by peroxyl addition onto the C8 of a vicinal purine base. In addition, the remaining 45% of the 8-oxodGuo are produced by an electron transfer reaction, providing an explanation for the higher yield of formation of 8-oxodGuo compared to 8-oxodAdo. Interestingly, we show that >40% of the 8-oxodGuo involved in tandem lesions is refractory to excision by DNA glycosylases. Altogether our results demonstrate that, subsequently to a single oxidation event, peroxidation reactions significantly increase the yield of formation of hydroxylated purine modifications, generating a high proportion of tandem lesions partly refractory to base excision repair.
关键词：DNA damage ; DNA repair ; peroxidation reaction ; tandem lesions
