CRISPR-Cas9 Screens Identify the RNA Helicase DDX3X as a Repressor of C9ORF72 (GGGGCC)n Repeat-Associated Non-AUG Translation

被引：96

作者：

Cheng, Weiwei ^{[1
,2
]}

Wang, Shaopeng ^{[1
,2
]}

Zhang, Zhe ^{[1
,2
]}

Morgens, David W. ^{[3
]}

Hayes, Lindsey R. ^{[2
,4
]}

Lee, Soojin ^{[5
]}

Portz, Bede ^{[6
]}

Xie, Yongzhi ^{[1
,2
]}

Nguyen, Baotram, V ^{[6
]}

Haney, Michael S. ^{[3
]}

Yan, Shirui ^{[1
,2
]}

Dong, Daoyuan ^{[1
,2
]}

Coyne, Alyssa N. ^{[2
,4
]}

Yang, Junhua ^{[7
]}

Xian, Fengfan ^{[1
,2
]}

Cleveland, Don W. ^{[8
,9
]}

Qiu, Zhaozhu ^{[7
]}

Rothstein, Jeffrey D. ^{[2
,4
]}

Shorter, James ^{[6
]}

Gao, Fen-Biao ^{[5
]}

Bassik, Michael C. ^{[3
]}

Sun, Shuying ^{[1
,2
]}

机构：

[1] Johns Hopkins Univ, Dept Pathol, Sch Med, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Brain Sci Inst, Sch Med, Baltimore, MD 21205 USA

[3] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA

[4] Johns Hopkins Univ, Dept Neurol, Sch Med, Baltimore, MD 21205 USA

[5] Univ Massachusetts, Dept Neurol, Med Sch, Worcester, MA 01605 USA

[6] Univ Penn, Dept Biochem & Biophys, Perelman Sch Med, Philadelphia, PA 19104 USA

[7] Johns Hopkins Univ, Dept Physiol, Sch Med, Baltimore, MD 21205 USA

[8] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA

[9] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA

来源：

NEURON | 2019年 / 104卷 / 05期

关键词：

HEXANUCLEOTIDE REPEAT; UNCONVENTIONAL TRANSLATION; ANTISENSE TRANSCRIPTS; FUNCTIONAL GENOMICS; GGGGCC REPEAT; EXPANSION; TOXICITY; PROTEINS; STRESS; FOCI;

D O I：

10.1016/j.neuron.2019.09.003

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Hexanucleotide GGGGCC repeat expansion in C9ORF72 is the most prevalent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). One pathogenic mechanism is the aberrant accumulation of dipeptide repeat (DPR) proteins produced by the unconventional translation of expanded RNA repeats. Here, we performed genome-wide CRISPR-Cas9 screens for modifiers of DPR protein production in human cells. We found that DDX3X, an RNA helicase, suppresses the repeat-associated non-AUG translation of GGGGCC repeats. DDX3X directly binds to (GGGGCC)n RNAs but not antisense (CCCCGG)n RNAs. Its helicase activity is essential for the translation repression. Reduction of DDX3X increases DPR levels in C9ORF72-ALS/FTD patient cells and enhances (GGGGCC)n-mediated toxicity in Drosophila. Elevating DDX3X expression is sufficient to decrease DPR levels, rescue nucleocytoplasmic transport abnormalities, and improve survival of patient iPSC-differentiated neurons. This work identifies genetic modifiers of DPR protein production and provides potential therapeutic targets for C9ORF72-ALS/FTD.

引用

页码：885 / +

页数：22

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