Spt4 Is Selectively Required for Transcription of Extended Trinucleotide Repeats
Spt4 Is Selectively Required for Transcription of Extended Trinucleotide Repeats
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DOI：
10.1016/j.cell.2011.12.032
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发表时间：
2012-02-17
期刊：
影响因子：
64.5
通讯作者：
Cheng, Tzu-Hao
中科院分区：
文献类型：
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作者：
Liu, Chia-Rung;Chang, Chuang-Rung;Cheng, Tzu-Hao
编码多聚谷氨酰胺（polyQ）的长三核苷酸重复序列是亨廷顿病和某些其他遗传性神经系统疾病的变异蛋白的特征。使用表型筛选来鉴定恢复S.在酿酒酵母中，我们发现转录延伸因子Spt 4需要转录位于DNA模板的ORF或非蛋白质编码区的长三核苷酸重复序列。SPT 4的突变选择性地降低了扩增的polyQ蛋白的合成并恢复了其酶活性，而不影响缺乏长polyQ延伸的蛋白。RNA-seq分析显示Spt 4对整体基因表达的影响有限。抑制哺乳动物的Spt 4同源物Supt 4 h，减少神经元细胞中的突变亨廷顿蛋白，并降低其聚集和毒性，同时不改变整体细胞mRNA的合成。我们的研究结果确定了通过重复的三核苷酸转录的细胞机制，以及针对扩展的三核苷酸区域引起的神经系统疾病的对策的潜在目标。
Lengthy trinucleotide repeats encoding polyglutamine (polyQ) stretches characterize the variant proteins of Huntington's disease and certain other inherited neurological disorders. Using a phenotypic screen to identify events that restore functionality to polyQ proteins in S. cerevisiae, we discovered that transcription elongation factor Spt4 is required to transcribe long trinucleotide repeats located either in ORFs or nonprotein-coding regions of DNA templates. Mutation of SPT4 selectively decreased synthesis of and restored enzymatic activity to expanded polyQ protein without affecting protein lacking long-polyQ stretches. RNA-seq analysis revealed limited effects of Spt4 on overall gene expression. Inhibition of Supt4h, the mammalian ortholog of Spt4, reduced mutant huntingtin protein in neuronal cells and decreased its aggregation and toxicity while not altering overall cellular mRNA synthesis. Our findings identify a cellular mechanism for transcription through repeated trinucleotides and a potential target for countermeasures against neurological disorders attributable to expanded trinucleotide regions.