Oxidative stress produces a variety of radicals in DNA, including pyrimidine nucleobase radicals. The nitrogen-centered DNA radical 2′-deoxycytidin-N4-yl radical (dC·) plays a role in DNA damage mediated by one electron oxidants, such as HOCl and ionizing radiation. However, the reactivity of dC· is not well understood. To reduce this knowledge gap, we photochemically generated dC· from a nitrophenyl oxime nucleoside and within chemically synthesized oligonucleotides from the same precursor. dC· formation is confirmed by transient UV-absorption spectroscopy in laser flash photolysis (LFP) experiments. LFP and duplex DNA cleavage experiments indicate that dC· oxidizes dG. Transient formation of the dG radical cation (dG^+•) is observed in LFP experiments. Oxidation of the opposing dG in DNA results in hole transfer when the opposing dG is part of a dGGG sequence. The sequence dependence is attributed to a competition between rapid proton transfer from dG^+• to the opposing dC anion formed and hole transfer. Enhanced hole transfer when less acidic O6-methyl-2′-deoxyguanosine is opposite dC· supports this proposal. dC· produces tandem lesions in sequences containing thymidine at the 5′-position by abstracting a hydrogen atom from the thymine methyl group. The corresponding thymidine peroxyl radical completes tandem lesion formation by reacting with the 5′-adjacent nucleotide. As dC· is reduced to dC, its role in the process is traceless and is only detectable because of the ability to independently generate it from a stable precursor. These experiments reveal that dC· oxidizes neighboring nucleotides, resulting in deleterious tandem lesions and hole transfer in appropriate sequences.

中文翻译：

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独立产生的 2'-脱氧胞苷-N4-基自由基的反应性和 DNA 损伤

氧化应激在 DNA 中产生多种自由基，包括嘧啶核碱基自由基。以氮为中心的 DNA 自由基 2'-脱氧胞苷-N 4-yl 自由基 (dC·) 在由一种电子氧化剂（如 HOCl 和电离辐射）介导的 DNA 损伤中发挥作用。然而，dC·的反应性还不是很清楚。为了缩小这一知识差距，我们从硝基苯肟核苷和从同一前体化学合成的寡核苷酸中光化学生成 dC·。在激光闪光光解 (LFP) 实验中，瞬态紫外吸收光谱证实了 dC· 的形成。LFP 和双链 DNA 切割实验表明 dC·氧化 dG。dG 自由基阳离子 (dG ^+•) 在 LFP 实验中观察到。当对立 dG 是 dGGG 序列的一部分时，DNA 中对立 dG 的氧化导致空穴转移。序列依赖性归因于质子从 dG ^+•到形成的相反 dC 阴离子的快速转移与空穴转移之间的竞争。在酸性较低的O时增强空穴传输6-methyl-2'-deoxyguanosine 与 dC·相反，支持这一提议。dC·通过从胸腺嘧啶甲基中提取一个氢原子，在 5' 位含有胸苷的序列中产生串联损伤。相应的胸苷过氧自由基通过与 5'-相邻核苷酸反应完成串联损伤形成。由于 dC·被还原为 dC，它在该过程中的作用是无迹可循的，并且只能检测到，因为它能够从稳定的前体中独立生成。这些实验表明，dC·氧化相邻的核苷酸，导致有害的串联损伤和适当序列中的空穴转移。