Peng Xiaohua, Pigli Ying Z, Rice Phoebe A, Greenberg Marc M
Department of Chemistry, The Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, USA.
J Am Chem Soc. 2008 Oct 1;130(39):12890-1. doi: 10.1021/ja805440v. Epub 2008 Sep 9.
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 significantly 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.
氧化性DNA损伤在衰老和多种疾病中具有重要作用。我们对自由基介导的DNA损伤化学的理解取得了重大进展。这些研究是在无蛋白质存在的情况下对DNA进行的。然而，在细胞中，DNA通常与染色质中的蛋白质结合，并被调节生化过程的蛋白质短暂结合。蛋白质结合如何以及是否会影响DNA自由基反应性尚不清楚。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)反应性的影响。Hbb使DNA弯曲并破坏扭结位点处的碱基堆积。当在Hbb存在的情况下于扭结位点产生1和2时，它们的反应性会受到显著影响。自由基构象流动性的增加导致DNA链间交联的产率显著提高。这些研究提供了关于蛋白质结合如何影响DNA自由基反应性的首批具体数据，使我们更接近于了解细胞中的氧化性DNA损伤。
