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EMBO J. 2019 Aug 1;38(15):e101341. doi: 10.15252/embj.2018101341. Epub 2019 Jul 4.

Defective ribosomal products challenge nuclear function by impairing nuclear condensate dynamics and immobilizing ubiquitin.

Author information

1
Centre for Neuroscience and Nanotechnology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
2
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
3
Genomic and post-Genomic Center, IRCCS Mondino Foundation, Pavia, Italy.
4
Technische Universität Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Biotechnology Center (BIOTEC), Dresden, Germany.

Abstract

Nuclear protein aggregation has been linked to genome instability and disease. The main source of aggregation-prone proteins in cells is defective ribosomal products (DRiPs), which are generated by translating ribosomes in the cytoplasm. Here, we report that DRiPs rapidly diffuse into the nucleus and accumulate in nucleoli and PML bodies, two membraneless organelles formed by liquid-liquid phase separation. We show that nucleoli and PML bodies act as dynamic overflow compartments that recruit protein quality control factors and store DRiPs for later clearance. Whereas nucleoli serve as constitutive overflow compartments, PML bodies are stress-inducible overflow compartments for DRiPs. If DRiPs are not properly cleared by chaperones and proteasomes due to proteostasis impairment, nucleoli undergo amyloidogenesis and PML bodies solidify. Solid PML bodies immobilize 20S proteasomes and limit the recycling of free ubiquitin. Ubiquitin depletion, in turn, compromises the formation of DNA repair compartments at fragile chromosomal sites, ultimately threatening cell survival.

KEYWORDS:

defective ribosomal products; membraneless organelles; molecular chaperones; nucleus; proteostasis

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