Huntingtin is a scaffolding protein in the ATM oxidative DNA damage response complex
Huntingtin is a scaffolding protein in the ATM oxidative DNA damage response complex
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DOI：
10.1093/hmg/ddw395
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发表时间：
2017-01-15
影响因子：
3.5
通讯作者：
Truant, Ray
中科院分区：
文献类型：
--
作者：
Maiuri, Tamara;Mocle, Andrew J.;Truant, Ray
亨廷顿氏病（HD）是一种年龄依赖性神经退行性疾病。DNA修复途径最近被认为是HD患者发病年龄最主要的改变因素。我们报道内源性亨廷顿蛋白直接参与DNA氧化损伤修复。利用新的染色体体检测活细胞中的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突变（ATM）蛋白的激酶活性。超分辨率显微镜和生化分析显示，亨廷顿蛋白与DNA损伤反应途径的蛋白共定位并支撑氧化应激。在具有典型临床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DNA损伤修复缺陷。我们认为，HD的DNA损伤是由突变的亨廷顿蛋白在DNA修复中的功能障碍引起的，而活性氧升高导致的DNA氧化损伤的积累可能有助于HD的发病。
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.