Mayo Clinic的研究人员和美国健康研究院以及挪威奥斯陆大学的研究人员合作发现，身体基因修复系统的一个错误可以导致亨廷顿症的发生。
亨廷顿舞蹈病(Huntington's disease,HD)是一种由IT15基因上CAG重复序列异常扩展所致常染色体显性遗传的神经退行性疾病。到目前为止，人们还不清楚这种疾病如何开始，只是知道它无法治愈。这项新发现发表在《自然》杂志的网络版上。
研究人员发现，当因氧化损伤引发的DNA中单链断裂被修复时，亨廷顿基因会连续添加多于的替代片段。经过一段时间，这种扩充（尤其在神经细胞中）产生了有害作用。
这些发现之所以具有重要意义是因为，人们目前对亨廷顿症还知之甚少。这项发现首次证实了DNA修复和这种疾病发生之间的联系。
研究中所使用的小鼠模型携带了人类亨廷顿基因。研究人员指出，这种大量重复的替代修复片段似乎到这些转基因小鼠4个月大时趋于稳定。在这个时间点之后，片段扩张并继续随着年龄的增加而增加。研究人员还证实这种片段的大量扩增还导致细胞毒性，使细胞不能增殖。
在进一步的研究中，研究组删除了一种与DNA修复有关的关键酶OGG1，并发现这种操作能终止或减少片段的增加。这个发现揭示出，OGG1可能作为干扰这种疾病发生的一个治疗性靶标候选。
原始出处:
Nature advance online publication 22 April 2007 | doi:10.1038/nature05778; Received 31 August 2006; Accepted 2 April 2007; Published online 22 April 2007
OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells
Irina V. Kovtun1, Yuan Liu5, Magnar Bjoras4, Arne Klungland4, Samuel H. Wilson5 & Cynthia T. McMurray1,2,3
Department of Pharmacology and Experimental Therapeutics,
Department of Biochemistry and Molecular Biology,
Neuroscience Program Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota 55905, USA
Centre for Molecular Biology and Neuroscience and Institute of Medical Microbiology, Rikshospitalet-Radiumhospitalet HF, University of Oslo, N-0027 Oslo, Norway
Laboratory of Structural Biology, National Institute of Environmental Health Sciences/National Institutes of Health, 111 TW Alexander Drive, Research Triangle Park, North Carolina 27709, USA
Correspondence to: Cynthia T. McMurray1,2,3 Correspondence and requests for materials should be addressed to C.T.M. (Email: mcmurray.cynthia@mayo.edu).
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Abstract
Although oxidative damage has long been associated with ageing and neurological disease, mechanistic connections of oxidation to these phenotypes have remained elusive. Here we show that the age-dependent somatic mutation associated with Huntington's disease occurs in the process of removing oxidized base lesions, and is remarkably dependent on a single base excision repair enzyme, 7,8-dihydro-8-oxoguanine-DNA glycosylase (OGG1). Both in vivo and in vitro results support a 'toxic oxidation' model in which OGG1 initiates an escalating oxidation–excision cycle that leads to progressive age-dependent expansion. Age-dependent CAG expansion provides a direct molecular link between oxidative damage and toxicity in post-mitotic neurons through a DNA damage response, and error-prone repair of single-strand breaks.
