Modification of DNA damage mechanisms by nitric oxide during ionizing radiation

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• 作者：Lisa K. Folkes ; Peter O'Neill ; ^{peter.oneill@oncology.ox.ac.uk}
• 关键词：dGMP ; 2&prime ; -deoxyguanosine monophosphate ; dG ; 2&prime ; -deoxyguanosine ; dXMP ; 2&prime ; -deoxyxanthosine monophosphate ; 8azadGMP ; 2&prime ; -deoxy-8-azaguanosine monophosphate ; 8oxodGMP ; 8-oxo-2&prime ; -deoxyguanosine monophosphate ; FaPydGMP ; (2&prime ; -deoxy
• 刊名：Free Radical Biology and Medicine
• 出版年：2013
• 出版时间：May, 2013
• 年：2013
• 卷：58
• 期：Complete
• 页码：14-25
• 全文大小：1139 K

文摘

Nitric oxide (^?NO) is a very effective radiosensitizer of hypoxic mammalian cells. In vivo ^?NO may have effects on tumor vasculature and hence on tumor oxygenation and it may also interact with radiation-produced radicals to modify DNA lesions. Few studies have addressed this last aspect, and we report here specific base modifications that result from reaction of ^?NO with radicals in DNA bases and in plasmid DNA after irradiation. 2¡ä-Deoxyxanthosine monophosphate and 2¡ä-deoxy-8-azaguanosine monophosphate (8azadGMP) are formed upon ¦Ã-irradiation of 2¡ä-deoxyguanosine monophosphate (dGMP) in the presence of micromolar levels of ^?NO in anoxia. In addition, the presence of ^?NO at physiological pH inhibits the formation of the well-described ^?OH-induced oxidation product of dGMP, 8-oxo-2¡ä-deoxyguanosine monophosphate. Single-strand breaks are induced in plasmid DNA when ¦Ã-irradiated in anoxia, whereas in the presence of ^?NO the number of breaks is reduced by approximately threefold, and evidence is shown for the formation of 8azadGMP in these plasmids. The consequence of the base modifications by ^?NO are as yet unknown although additional breaks are revealed in irradiated plasmid DNA after treatment with glycosylases involved in base excision repair. V79-4 cells irradiated in anoxia show an enhancement in the number of ¦ÃH2AX foci when ^?NO is present, particularly evident a few hours postirradiation, indicative of the formation of replication-induced DNA damage. We propose that the consequence of ^?NO-induced base modifications in anoxia contributes to its radiosensitization of cells.