Drake Jennifer, Petroze Robin, Castegna Alessandra, Ding Qunxing, Keller Jeffrey N, Markesbery William R, Lovell Mark A, Butterfield D Allan
Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA.
Neurosci Lett. 2004 Feb 19;356(3):155-8. doi: 10.1016/j.neulet.2003.11.047.
There is increasing evidence of DNA oxidation and altered DNA repair mechanisms in Alzheimer's disease (AD) brain. Histones, which interact with DNA, conceivably could provide a protective shield for DNA against oxidative stress. However, because of their abundant lysine residues, histones may be a target for 4-hydroxynonenal (HNE) modification. In this study, we have shown that HNE binds to histones and that this binding affects the conformation of the histone, measured by electron paramagnetic resonance in conjunction with a protein-specific spin label. The covalent modification to the histone by HNE affects the ability of the histone to bind DNA. Interestingly, acetylated histones appear to be more susceptible to HNE modifications than control histones. Conceivably, altered DNA-histone interactions, subsequent to oxidative modification of histones by the lipid peroxidation product HNE, may contribute to the vulnerability of DNA to oxidation in AD brain.
越来越多的证据表明，阿尔茨海默病（AD）大脑中存在DNA氧化和DNA修复机制改变的情况。与DNA相互作用的组蛋白，可以想象能够为DNA提供抵御氧化应激的保护屏障。然而，由于组蛋白富含赖氨酸残基，它们可能成为4-羟基壬烯醛（HNE）修饰的靶点。在本研究中，我们已经表明HNE与组蛋白结合，并且这种结合会影响组蛋白的构象，这是通过电子顺磁共振结合蛋白质特异性自旋标记来测量的。HNE对组蛋白的共价修饰会影响组蛋白与DNA结合的能力。有趣的是，乙酰化组蛋白似乎比对照组蛋白更容易受到HNE修饰的影响。可以想象，脂质过氧化产物HNE对组蛋白进行氧化修饰后，DNA-组蛋白相互作用的改变可能导致AD大脑中DNA对氧化的易感性增加。
