Maiuri Tamara, Mocle Andrew J, Hung Claudia L, Xia Jianrun, van Roon-Mom Willeke M C, Truant Ray
Department of Biochemistry and Biomedical Research, McMaster University, HSC 4N54, 1200 Main Street West, Hamilton, Canada L8N3Z5.
Center for Human and Clinical Genetics, Leiden University Medical Center, Postzone S4-0P, P.O. Box 9600 2300RC Leiden, The Netherlands.
Hum Mol Genet. 2017 Jan 15;26(2):395-406. doi: 10.1093/hmg/ddw395.
Huntington's disease (HD) is an age-dependent neurodegenerative disease. DNA repair pathways have recently been implicated as the most predominant modifiers of age of onset in HD patients. We report that endogenous huntingtin protein directly participates in oxidative DNA damage repair. Using novel chromobodies to detect endogenous human huntingtin in live cells, we show that localization of huntingtin to DNA damage sites is dependent on the kinase activity of ataxia telangiectasia mutated (ATM) protein. Super-resolution microscopy and biochemical assays revealed that huntingtin co-localizes with and scaffolds proteins of the DNA damage response pathway in response to oxidative stress. In HD patient fibroblasts bearing typical clinical HD allele lengths, we demonstrate that there is deficient oxidative DNA damage repair. We propose that DNA damage in HD is caused by dysfunction of the mutant huntingtin protein in DNA repair, and accumulation of DNA oxidative lesions due to elevated reactive oxygen species may contribute to the onset of HD.
亨廷顿舞蹈症（HD）是一种与年龄相关的神经退行性疾病。DNA修复途径最近被认为是HD患者发病年龄的最主要调节因子。我们报告称，内源性亨廷顿蛋白直接参与氧化性DNA损伤修复。利用新型染色体体在活细胞中检测内源性人类亨廷顿蛋白，我们发现亨廷顿蛋白在DNA损伤位点的定位依赖于共济失调毛细血管扩张症突变（ATM）蛋白的激酶活性。超分辨率显微镜和生化分析表明，在氧化应激反应中，亨廷顿蛋白与DNA损伤反应途径的蛋白共定位并构成支架。在携带典型临床HD等位基因长度的HD患者成纤维细胞中，我们证明存在氧化性DNA损伤修复缺陷。我们提出，HD中的DNA损伤是由DNA修复中突变亨廷顿蛋白功能障碍引起的，并且由于活性氧升高导致的DNA氧化损伤积累可能促成HD的发病。
