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Science. 2018 May 25;360(6391):918-921. doi: 10.1126/science.aar7366. Epub 2018 Apr 12.

RNA buffers the phase separation behavior of prion-like RNA binding proteins.

Author information

1
Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstraße 108, 01307 Dresden, Germany.
2
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
3
B Cube-Center for Molecular Bioengineering, Technische Universität Dresden, Arnoldstraße 18, 01307 Dresden, Germany.
4
Biotechnology Center, Technische Universität Dresden, Tatzberg 47/49, 01307 Dresden, Germany.
5
Technische Universität Dresden-Center for Molecular and Cellular Bioengineering (CMCB), DFG-Center for Regenerative Therapies Dresden, 01307 Dresden, Germany.
6
Center for Self-Assembly and Complexity, Institute for Basic Science (IBS), Pohang 37673, Republic of Korea.
7
Department of Chemistry, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea.
8
Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstraße 108, 01307 Dresden, Germany. alberti@mpi-cbg.de hyman@mpi-cbg.de.

Abstract

Prion-like RNA binding proteins (RBPs) such as TDP43 and FUS are largely soluble in the nucleus but form solid pathological aggregates when mislocalized to the cytoplasm. What keeps these proteins soluble in the nucleus and promotes aggregation in the cytoplasm is still unknown. We report here that RNA critically regulates the phase behavior of prion-like RBPs. Low RNA/protein ratios promote phase separation into liquid droplets, whereas high ratios prevent droplet formation in vitro. Reduction of nuclear RNA levels or genetic ablation of RNA binding causes excessive phase separation and the formation of cytotoxic solid-like assemblies in cells. We propose that the nucleus is a buffered system in which high RNA concentrations keep RBPs soluble. Changes in RNA levels or RNA binding abilities of RBPs cause aberrant phase transitions.

Comment in

PMID:
29650702
PMCID:
PMC6091854
DOI:
10.1126/science.aar7366
[Indexed for MEDLINE]
Free PMC Article

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