OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells
OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells
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DOI：
10.1038/nature05778
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发表时间：
2007-05-24
期刊：
影响因子：
64.8
通讯作者：
McMurray, Cynthia T.
中科院分区：
文献类型：
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作者：
Kovtun, Irina V.;Liu, Yuan;McMurray, Cynthia T.
虽然氧化损伤长期以来一直与衰老和神经系统疾病有关，但氧化与这些表型的机械联系仍然难以捉摸。在这里，我们表明，与亨廷顿病相关的年龄依赖性体细胞突变发生在去除氧化碱基损伤的过程中，并显着依赖于单碱基切除修复酶，7，8-二氢-8-氧代鸟嘌呤-DNA糖基化酶（OGG 1）。体内和体外结果均支持“毒性氧化”模型，其中OGG 1启动逐步升级的氧化-切除循环，导致进行性年龄依赖性扩增。通过DNA损伤反应和单链断裂的易错修复，β-依赖性CAG扩增提供了有丝分裂后神经元中氧化损伤和毒性之间的直接分子联系。
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.