Darbinyan Armine, White Martyn K, Akan Selma, Radhakrishnan Sujatha, Del Valle Luis, Amini Shohreh, Khalili Kamel
Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, PA 19122, USA.
Virology. 2007 Jul 20;364(1):73-86. doi: 10.1016/j.virol.2007.02.015. Epub 2007 Mar 21.
Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disorder of the CNS caused by infection of glial cells with the polyomavirus, JCV. Here we report that genomic stability and DNA repair are significantly dysregulated by JCV infection of human astrocytes. Metaphase spreads exhibited increased ploidy correlating with duration of infection. Increased micronuclei formation and phospho-Histone2AX expression also indicated DNA damage. Western blot analysis revealed perturbation in expression of some DNA repair proteins including a large elevation of Rad51. Immunohistochemistry on clinical samples of PML showed robust labeling for Rad51 in nuclei of bizarre astrocytes and inclusion body-bearing oligodendrocytes that are characteristic of JCV infection. Finally, in vitro end-joining DNA repair was altered in extracts prepared from JCV-infected human astrocytes. Alterations in DNA repair pathways may be important for the life cycle of JCV and the pathogenesis of PML.
进行性多灶性白质脑病（PML）是一种由多瘤病毒JCV感染神经胶质细胞引起的致命性中枢神经系统脱髓鞘疾病。在此我们报告，人星形胶质细胞被JCV感染后，基因组稳定性和DNA修复功能会显著失调。中期染色体铺展显示，多倍体增加与感染持续时间相关。微核形成增加和磷酸化组蛋白H2AX表达增加也表明存在DNA损伤。蛋白质免疫印迹分析显示，一些DNA修复蛋白的表达受到干扰，包括Rad51大幅升高。对PML临床样本进行的免疫组织化学分析显示，在JCV感染所特有的奇异星形胶质细胞核和含包涵体的少突胶质细胞中，Rad51有强烈标记。最后，从JCV感染的人星形胶质细胞制备的提取物中，体外末端连接DNA修复功能发生了改变。DNA修复途径的改变可能对JCV的生命周期和PML的发病机制很重要。
