Neil1 is a genetic modifier of somatic and germline CAG trinucleotide repeat instability in R6/1 mice.
Neil1 is a genetic modifier of somatic and germline CAG trinucleotide repeat instability in R6/1 mice.
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DOI：
10.1093/hmg/dds337
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发表时间：
2012-11-15
影响因子：
3.5
通讯作者：
Klungland A
中科院分区：
文献类型：
--
作者：
Møllersen L;Rowe AD;Illuzzi JL;Hildrestrand GA;Gerhold KJ;Tveterås L;Bjølgerud A;Wilson DM 3rd;Bjørås M;Klungland A
亨廷顿病 (HD) 是一种由三核苷酸重复 (TNR) 扩增引起的进行性神经退行性疾病。我们在此表明，与 R6/1/Neil1+/+ 小鼠相比，缺乏 Nei-like 1 (Neil1) 外显子 2 (R6/1/Neil1−/−) 的 R6/1 小鼠的几个器官的体细胞 TNR 扩增显着减少。体细胞 TNR 扩展通过两种不同的方法测量，即平均重复变化和不稳定指数。雄性 R6/1/Neil1−/− 小鼠的体细胞扩张减少更为明显，而雌性 R6/1/Neil1−/− 小鼠的大脑区域的扩张也显着减少。此外，我们发现功能性 Neil1 的缺乏显着降低了 R6/1 雄性小鼠的种系扩增。在体外，纯化的人 NEIL1 蛋白比发夹底物更有效地结合和切除双链 DNA 中的 5-羟基胞嘧啶。因此，NEIL1 切除胞嘧啶衍生的氧化损伤可能参与启动 TNR 扩增过程，尽管其他 DNA 修饰也可能有所贡献。总而言之，这些结果表明 Neil1 有助于种系和体细胞 HD CAG 重复扩增。
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by trinucleotide repeat (TNR) expansions. We show here that somatic TNR expansions are significantly reduced in several organs of R6/1 mice lacking exon 2 of Nei-like 1 (Neil1) (R6/1/Neil1−/−), when compared with R6/1/Neil1+/+ mice. Somatic TNR expansion is measured by two different methods, namely mean repeat change and instability index. Reduced somatic expansions are more pronounced in male R6/1/Neil1−/− mice, although expansions are also significantly reduced in brain regions of female R6/1/Neil1−/− mice. In addition, we show that the lack of functional Neil1 significantly reduces germline expansion in R6/1 male mice. In vitro, purified human NEIL1 protein binds and excises 5-hydroxycytosine in duplex DNA more efficiently than in hairpin substrates. NEIL1 excision of cytosine-derived oxidative lesions could therefore be involved in initiating the process of TNR expansion, although other DNA modifications might also contribute. Altogether, these results imply that Neil1 contributes to germline and somatic HD CAG repeat expansion.
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