Large-scale expansions of Friedreich's ataxia GAA repeats in yeast.
Large-scale expansions of Friedreich's ataxia GAA repeats in yeast.
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DOI：
10.1016/j.molcel.2009.06.017
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发表时间：
2009-07-10
期刊：
影响因子：
16
通讯作者：
Mirkin, Sergei M.
中科院分区：
文献类型：
--
作者：
Shishkin, Alexander A.;Voineagu, Irina;Matera, Robert;Cherng, Nicole;Chernet, Brook T.;Krasilnikova, Maria M.;Narayanan, Vidhya;Lobachev, Kirill S.;Mirkin, Sergei M.
DNA重复序列的大规模扩增与人类的许多遗传性疾病有关。我们描述了一种酵母实验系统来分析三重GAA重复序列的大规模扩增，该重复序列是人类疾病弗里德赖希共济失调的原因。当将GAA重复序列插入嵌合URA3基因的内含子中时，它们的扩增导致基因失活，这在选择性培养基上检测到。我们发现GAA重复序列的扩增率随其长度呈指数增长。这些速率仅轻微地依赖于复制子内的重复序列的方向，而重复序列介导的复制叉停滞是精确地依赖于方向的。扩增速率显着升高后，失活的复制叉稳定剂，TOF 1和CSM 3，但减少了在突变体的复制后DNA修复蛋白，Rad6和Rad5，和DNA解旋酶SGS 1。我们提出了一个大规模的重复扩增模型的基础上的模板切换过程中的复制叉进展通过重复DNA。
Large-scale expansions of DNA repeats are implicated in numerous hereditary disorders in humans. We describe a yeast experimental system to analyze large-scale expansions of triplet GAA repeats, responsible for the human disease Friedreich’s ataxia. When GAA repeats were placed into an intron of the chimeric URA3 gene, their expansions caused gene inactivation, which was detected on the selective media. We found that the rates of expansions of GAA repeats increased exponentially with their lengths. These rates were only mildly dependent on the repeat’s orientation within the replicon, whereas the repeat-mediated replication fork stalling was exquisitely orientation-dependent. Expansion rates were significantly elevated upon inactivation of the replication fork stabilizers, Tof1 and Csm3, but decreased in the mutants of postreplication DNA repair proteins, Rad6 and Rad5, and the DNA helicase Sgs1. We propose a model for large-scale repeat expansions based on the template switching during the replication fork progression through repetitive DNA.
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