Efficient DNA interstrand cross-link formation from a nucleotide radical
Efficient DNA interstrand cross-link formation from a nucleotide radical
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DOI：
10.1021/ja042434q
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发表时间：
2005-03-23
影响因子：
15
通讯作者：
Greenberg, MM
中科院分区：
文献类型：
--
作者：
Hong, IS;Greenberg, MM
5-（2 '-脱氧尿苷基）甲基自由基（1）在DNA的γ辐射和其他氧化应激方法中产生。这种反应性中间体在双链体中的独立产生导致显著水平的DNA链间交联。交联形成不需要O2，并且涉及最初产生自由基的核苷酸与相对的脱氧腺苷之间的反应。这是第一个核苷酸自由基的形成最终导致DNA-DNA交联的例子。链间DNA交联难以修复，并且被认为是抗肿瘤剂（如丝裂霉素C）的细胞毒性的来源。通过1的DNA交联的有效形成应该为利用该途径的DNA损伤剂的设计提供动力。
5-(2‘-Deoxyuridinyl)methyl radical (1) is produced during γ-irradiation of DNA and other methods of oxidative stress. Independent generation of this reactive intermediate in duplex results in significant levels of DNA interstrand cross-links. Cross-link formation does not require O2and involves reaction between the nucleotide where the radical is originally generated and the opposing deoxyadenosine. This is the first example in which formation of a nucleotide radical ultimately results in DNA−DNA cross-links. Interstrand DNA cross-links are difficult to repair and are believed to be the source of cytotoxicity of antitumor agents, such as mitomycin C. The efficient formation of DNA cross-links through1should provide the impetus for the design of DNA damaging agents that exploit this pathway.