In DNA, 2′-deoxyguanosine (dG) is susceptible to oxidative modification by reactive oxygen species (ROS) yielding many products, one of which is 8-oxo-7,8-dihydro-2′-deoxyguanosine (dOG). Interestingly, dOG is stable but much more labile toward oxidation than dG, furnishing 5-guanidinohydantoin-2′-deoxyribose (dGh) that is favored in the duplex context or spiroiminodihydantoin-2′-deoxyribose (dSp) that is favored in the oxidation of single-stranded contexts. Previously, exposure of DNA to ionizing radiation found ∼50% of the dOG exists as a tandem lesion with an adjacent formamide site. The present work explored oxidation of dOG in a tandem lesion with a THF abasic site analog (F) that models the formamide on either the 5′ or 3′ side. When dOG was in a tandem lesion, both dGh and dSp were observed as oxidation products. The 5′ versus 3′ side in which F resided influenced the stereochemistry of the dSp formed. Further, tandem lesions with dOG were found to be up to two orders of magnitude more reactive to oxidation than dOG in an intact duplex. When dOG is in a tandem lesion it is up to fivefold more prone to formation of spermine cross-links during oxidation compared to dOG in an intact duplex. Lastly, dOG, dGh, and each dSp diastereomer were synthesized as part of a tandem lesion in a duplex DNA to establish that dOG tandem lesions decrease the thermal stability by 12–13 °C, while dGh or either dSp diastereomer in a tandem lesion decrease the stability by >20 °C. The biological consequences of these results are discussed.

中文翻译：

---

8-Oxo-7,8-dihydro-2'-deoxyguanosine和无碱基串联损伤是易氧化的乙内酰脲产品，会严重破坏双链DNA的稳定性

在DNA中，2'-脱氧鸟苷（dG）易受活性氧（ROS）氧化修饰而产生许多产物，其中之一是8-oxo-7,8-dihydro-2'-deoxyguanosine（dOG）。有趣的是，dOG稳定，但比dG氧化更不稳定，提供了在双链环境下较受青睐的5-胍基海因2'-脱氧核糖（dGh）或在氧化过程中偏向于提供的螺胺基二乙内酰脲2'-脱氧核糖（dSp）。单链上下文。以前，DNA暴露于电离辐射中，发现约50％的dOG以串联形式存在，并带有相邻的甲酰胺位。本工作探索了在串联损伤中用THF脱碱基位点类似物（F）在5'或3'侧建模甲酰胺对dOG的氧化作用。当dOG处于串联病变中时，dGh和dSp均被观察为氧化产物。5'相对于其中F存在的3'侧影响形成的dSp的立体化学。此外，发现在完整的双链体中，具有dOG的串联损伤比dOG对氧化的反应性高多达两个数量级。当dOG处于串联病变中时，与完整双链体中的dOG相比，氧化过程中形成精胺交联的可能性高出五倍。最后，将dOG，dGh和每个dSp非对映异构体合成为双链DNA中串联损伤的一部分，以建立dOG串联损伤使热稳定性降低12–13°C，而dGh或dSp非对映异构体在串联损伤中降低> 20°C时的稳定性。讨论了这些结果的生物学后果。