Toxic expanded GGGGCC repeat transcription is mediated by the PAF1 complex in C9orf72-associated FTD
Toxic expanded GGGGCC repeat transcription is mediated by the PAF1 complex in C9orf72-associated FTD
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DOI：
10.1038/s41593-019-0396-1
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发表时间：
2019-06-01
影响因子：
25
通讯作者：
Bonini, Nancy M.
中科院分区：
文献类型：
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作者：
Goodman, Lindsey D.;Prudencio, Mercedes;Bonini, Nancy M.
在C9 orf 72内超过30个重复的扩展GGGGCC六核苷酸（称为（G4 C2）（30+））是家族性额颞叶变性（FTD）和肌萎缩侧索硬化（ALS）（称为C9（+））中最突出的突变。通过对表达（G4 C2）（49）的果蝇进行无偏见的大规模筛选，我们鉴定出CDC 73/PAF 1复合物（PAF 1C），一种RNA聚合酶II的转录调节因子，在被敲低时作为G4 C2相关毒性的抑制因子。PAF 1C的消耗减少了来自（G4 C2）（30+）转基因的RNA和GR二肽的产生。值得注意的是，在果蝇中，PAF 1C组分Pafl和Leo 1似乎对长的、有毒的重复扩增的转录具有选择性，但对短的、无毒的扩增没有选择性。在酵母中，PAF 1C组分调节正义和反义重复序列的表达。PAF 1C在果蝇和小鼠中（G4 C2）（30+）表达后上调。在人类中，PAF 1在C9（+）衍生细胞中也上调，其异二聚体伴侣LEO 1结合C9（+）重复染色质。在C9（+）FTD中，PAF 1和LEO 1上调，其表达与含重复序列的C9 orf 72转录本的表达呈正相关。这些数据表明，PAF 1C活性是C9（+）FTD中长毒性重复序列转录的重要因素。
An expanded GGGGCC hexanucleotide of more than 30 repeats (termed (G4C2)(30+)) within C9orf72 is the most prominent mutation in familial frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) (termed C9(+)). Through an unbiased large-scale screen of (G4C2)(49)-expressing Drosophila we identify the CDC73/PAF1 complex (PAF1C), a transcriptional regulator of RNA polymerase II, as a suppressor of G4C2-associated toxicity when knocked-down. Depletion of PAF1C reduces RNA and GR dipeptide production from (G4C2)(30+) transgenes. Notably, in Drosophila, the PAF1C components Pafl and Leo1 appear to be selective for the transcription of long, toxic repeat expansions, but not shorter, nontoxic expansions. In yeast, PAF1C components regulate the expression of both sense and antisense repeats. PAF1C is upregulated following (G4C2)(30+) expression in flies and mice. In humans, PAF1 is also upregulated in C9(+)-derived cells, and its heterodimer partner, LEO1, binds C9(+) repeat chromatin. In C9(+) FTD, PAF1 and LEO1 are upregulated and their expression positively correlates with the expression of repeat-containing C9orf72 transcripts. These data indicate that PAF1C activity is an important factor for transcription of the long, toxic repeat in C9(+) FTD.