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Mol Cell. 2018 Mar 1;69(5):787-801.e8. doi: 10.1016/j.molcel.2018.02.001.

FUS Regulates Activity of MicroRNA-Mediated Gene Silencing.

Author information

1
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
2
Department of Biology, Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD 21218, USA.
3
Department of Biophysics, Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD 21218, USA.
4
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Keck Structural Biology Laboratory, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
6
Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
7
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
8
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: jiouw@jhu.edu.

Abstract

MicroRNA-mediated gene silencing is a fundamental mechanism in the regulation of gene expression. It remains unclear how the efficiency of RNA silencing could be influenced by RNA-binding proteins associated with the microRNA-induced silencing complex (miRISC). Here we report that fused in sarcoma (FUS), an RNA-binding protein linked to neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), interacts with the core miRISC component AGO2 and is required for optimal microRNA-mediated gene silencing. FUS promotes gene silencing by binding to microRNA and mRNA targets, as illustrated by its action on miR-200c and its target ZEB1. A truncated mutant form of FUS that leads its carriers to an aggressive form of ALS, R495X, impairs microRNA-mediated gene silencing. The C. elegans homolog fust-1 also shares a conserved role in regulating the microRNA pathway. Collectively, our results suggest a role for FUS in regulating the activity of microRNA-mediated silencing.

KEYWORDS:

AGO2; ALS; Argonaute; C. elegans; FTD; FUS; RNA; gene silencing; microRNA; neurodegeneration

PMID:
29499134
PMCID:
PMC5836505
DOI:
10.1016/j.molcel.2018.02.001
[Indexed for MEDLINE]
Free PMC Article

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