Protein binding has a large effect on radical mediated DNA damage
Protein binding has a large effect on radical mediated DNA damage
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DOI：
10.1021/ja805440v
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发表时间：
2008-10-01
影响因子：
15
通讯作者：
Greenberg, Marc M.
中科院分区：
文献类型：
--
作者：
Peng, Xiaohua;Pigli, Ying Z.;Greenberg, Marc M.
氧化性DNA损伤在衰老和多种疾病中很重要。在我们对自由基介导的DNA损伤的化学理解方面已经取得了重大进展。这些研究是在没有蛋白质的情况下对DNA进行的。然而，在细胞中，DNA通常被蛋白质结合，例如在染色质中，并且短暂地被调节生物化学过程的蛋白质结合。蛋白质结合如何以及是否影响DNA自由基的反应性还没有很好的理解，研究了DNA结合蛋白Hbb对5-（2 '-脱氧尿苷基）甲基自由基（1）和5-（2'-脱氧胞苷基）甲基自由基（2）的反应性的影响。Hbb使DNA弯曲并破坏扭结位点的碱基堆积。当它们在Hbb存在下在扭结位点产生时，1和2的反应性受到显著影响。这些研究提供了关于蛋白质结合如何影响DNA自由基的反应性的第一个具体数据，并使我们更接近于理解细胞中的氧化DNA损伤。
Oxidative DNA damage is important in aging and a variety of diseases. Significant advances have been made in our understanding of the chemistry of radical mediated DNA damage. These studies have been carried out on DNA in the absence of proteins. However, in cells DNA is typically bound by proteins such as in chromatin and transiently by proteins that regulate biochemical processes. How and whether protein binding affects DNA radical reactivity is not well understood, The effect of the DNA binding protein Hbb on the reactivity of the 5-(2'-deoxyuridinyl)methyl radical (1) and 5-(2'-deoxycytidinyl)methyl radical (2) was studied. Hbb bends DNA and disrupts base stacking at the sites of kinking. The reactivity of 1 and 2 are signficantly affected when they are generated at the kinking site in the presence of Hbb. The increased conformational mobility of the radicals results in significantly higher yields of DNA interstrand cross-links, These studies provide the first specific data on how protein binding affects the reactivity of a DNA radical and bring us closer to understanding oxidative DNA damage in cells.