CAG*CTG repeat instability in cultured human astrocytes.
CAG*CTG repeat instability in cultured human astrocytes.
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DOI：
10.1093/nar/gkl614
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发表时间：
2006
影响因子：
14.9
通讯作者：
Lahue RS
中科院分区：
文献类型：
--
作者：
Farrell BT;Lahue RS
中枢神经系统（CNS）的细胞易于遭受三核苷酸重复序列（TNR）扩增的破坏性后果。一些CNS细胞，包括星形胶质细胞，在受影响的个体中显示出显著的TNR不稳定性。由于星形胶质细胞富集发生在对神经变性和体细胞TNR不稳定性敏感的脑区域中，因此使用永生化SVG-A星形胶质细胞作为离体模型来模拟TNR诱变。培养的星形胶质细胞以序列特异性方式产生频繁的（高达2%）CAG·CTG收缩，并且在25和33个重复之间观察到明显的不稳定性阈值。这些结果表明，培养的星形胶质细胞概括了TNR诱变的关键特征。此外，收缩受到DNA复制的影响，通过重复，这表明不稳定性可能会出现在这些细胞中的复制为基础的机制。这是一个关键的机制点，因为CNS中的星形胶质细胞在整个生命过程中保持增殖能力，并且可能容易受到复制介导的TNR不稳定性的影响。与单纯的重复相比，中断的存在导致更小但更频繁的收缩，有时中断被删除以形成完美的管道。综上所述，我们认为培养的星形胶质细胞中CAG·CTG重复序列的不稳定性是动态的和复制驱动的，提示TNR突变可能受到关键CNS细胞增殖能力的影响。
Cells of the central nervous system (CNS) are prone to the devastating consequences of trinucleotide repeat (TNR) expansion. Some CNS cells, including astrocytes, show substantial TNR instability in affected individuals. Since astrocyte enrichment occurs in brain regions sensitive to neurodegeneration and somatic TNR instability, immortalized SVG-A astrocytes were used as an ex vivo model to mimic TNR mutagenesis. Cultured astrocytes produced frequent (up to 2%) CAG·CTG contractions in a sequence-specific fashion, and an apparent threshold for instability was observed between 25 and 33 repeats. These results suggest that cultured astrocytes recapitulate key features of TNR mutagenesis. Furthermore, contractions were influenced by DNA replication through the repeat, suggesting that instability can arise by replication-based mechanisms in these cells. This is a crucial mechanistic point, since astrocytes in the CNS retain proliferative capacity throughout life and could be vulnerable to replication-mediated TNR instability. The presence of interruptions led to smaller but more frequent contractions, compared to a pure repeat, and the interruptions were sometimes deleted to form a perfect tract. In summary, we suggest that CAG·CTG repeat instability in cultured astrocytes is dynamic and replication-driven, suggesting that TNR mutagenesis may be influenced by the proliferative capacity of key CNS cells.
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影响因子：
3.5
作者：
Heffron, DS;Mandell, JW
通讯作者：
Mandell, JW
影响因子：
14.9
作者：
Dixon, MJ;Lahue, RS
通讯作者：
Lahue, RS
影响因子：
14.9
作者：
Mitas, M
通讯作者：
Mitas, M
影响因子：
3.5
作者：
Mornet, E;Chateau, C;Serre, JL
通讯作者：
Serre, JL
DOI：
10.1073/pnas.95.21.12438
发表时间：
1998-10-13
影响因子：
11.1
作者：
Miret, JJ;Pessoa-Brandao, L;Lahue, RS
通讯作者：
Lahue, RS