Reactivity and DNA Damage by Independently Generated 2'-Deoxycytidin-N4-yl Radical.
Reactivity and DNA Damage by Independently Generated 2'-Deoxycytidin-N4-yl Radical.
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DOI：
10.1021/jacs.1c06425
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发表时间：
2021-09-15
影响因子：
15
通讯作者：
Greenberg MM
中科院分区：
文献类型：
--
作者：
Peng H;Jie J;Mortimer IP;Ma Z;Su H;Greenberg MM
氧化应激在DNA中产生各种自由基，包括嘧啶核酸基。以氮为中心的DNA自由基2‘-脱氧胞苷-N4-基(DC·)在HOCl和电离辐射等单电子氧化剂介导的DNA损伤中起着重要作用。然而，DC·的反应性还不是很清楚。为了缩小这一知识差距，我们从一种硝基苯肟核苷中光化学合成了DC·，并在化学合成的同一前体的寡核苷酸中生成了DC·。激光闪光光解(LFP)实验中的瞬时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。在LFP实验中观察到DG自由基阳离子(DG+·)的瞬时形成。当相反的DG是dGGG序列的一部分时，DNA中相反的DG的氧化会导致空穴转移。这种顺序依赖性归因于从DG+·到相反的直流阴离子的快速质子转移和空穴转移之间的竞争。当酸性较弱的O6-甲基-2‘-脱氧鸟苷相反时，增强了空穴转移，DC·支持这一提议。DC·通过从胸腺嘧啶甲基中提取氢原子，在5‘-位含有胸腺嘧啶核苷的序列中产生串联损伤。相应的胸苷过氧基通过与5‘-相邻的核苷酸反应完成串联损伤的形成。由于DC·被还原为DC，其在该过程中的作用是无法追踪的，只有通过从稳定的前体独立产生它的能力才能被检测到。这些实验表明，DC·氧化邻近的核苷酸，导致有害的串联损伤和适当序列的空穴转移。
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.
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影响因子：
2.9
作者：
Huang, Haidong;Imoto, Shuhei;Greenberg, Marc M.
通讯作者：
Greenberg, Marc M.
影响因子：
4.1
作者：
Hawkins, CL;Davies, MJ
通讯作者：
Davies, MJ
影响因子：
4.1
作者：
Hawkins, CL;Davies, MJ
通讯作者：
Davies, MJ
影响因子：
15
作者：
Anderson, Robert F.;Shinde, Sujata S.;Maroz, Andrej
通讯作者：
Maroz, Andrej
影响因子：
15
作者：
Carter, KN;Greenberg, MM
通讯作者：
Greenberg, MM