The Nucleolus: A Multiphase Condensate Balancing Ribosome Synthesis and Translational Capacity in Health, Aging and Ribosomopathies.

Carl C Correll,Jiri Bartek,Miroslav Dundr

doi:10.3390/cells8080869

Carl C Correll, Jiri Bartek + Show 1 more

Open Access

https://doi.org/10.3390/cells8080869

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Journal: Cells	Publication Date: Aug 10, 2019
Citations: 88	License type: CC BY 4.0

Affiliation: Rosalind Franklin University of Medicine and Science

Abstract

The nucleolus is the largest membrane-less structure in the eukaryotic nucleus. It is involved in the biogenesis of ribosomes, essential macromolecular machines responsible for synthesizing all proteins required by the cell. The assembly of ribosomes is evolutionarily conserved and is the most energy-consuming cellular process needed for cell growth, proliferation, and homeostasis. Despite the significance of this process, the intricate pathophysiological relationship between the nucleolus and protein synthesis has only recently begun to emerge. Here, we provide perspective on new principles governing nucleolar formation and the resulting multiphase organization driven by liquid-liquid phase separation. With recent advances in the structural analysis of ribosome formation, we highlight the current understanding of the step-wise assembly of pre-ribosomal subunits and the quality control required for proper function. Finally, we address how aging affects ribosome genesis and how genetic defects in ribosome formation cause ribosomopathies, complex diseases with a predisposition to cancer.

Highlights

The ribosome is fundamental to cellular function, serving as the site for protein synthesis
Ribosome production and protein translation are tightly coordinated to ensure that the number of ribosomes supports the demands for protein synthesis associated with cell growth and proliferation
We focus on recent progress elucidating the role of liquid-liquid phase separation in the formation of the nucleolus, the functional multiphase sub-organization of the nucleolus, the epigenetic regulation of rDNA gene expression, and the structure and function of the pre-ribosomal RNAs (rRNAs) processing machinery

Summary

Introduction

The ribosome is fundamental to cellular function, serving as the site for protein synthesis. The resulting production of the 47S pre-rRNA precursor initiates nucleation of the nucleolus around the ribosomal genes within the cell nucleus. Trans-acting AFs coordinate stepwise and hierarchical modifications, processing and folding of the 47S pre-rRNA precursor, and its assembly with r-proteins. Cells 2019, 8, 869 control ensures that only active ribosomal subunits are released. From this perspective, we focus on recent progress elucidating the role of liquid-liquid phase separation in the formation of the nucleolus, the functional multiphase sub-organization of the nucleolus, the epigenetic regulation of rDNA gene expression, and the structure and function of the pre-rRNA processing machinery. We examine the pathophysiological links between ribosome biogenesis, the nucleolus, aging, and ribosomopathies

Phase Separation and the Dynamic Nature of the Nucleolus

The location arm of of human humanchromosome chromosome1 1and and the

Organization of Ribosomal Genes

Ribosomal Genes and Genomic Instability

Structural Insights on Pre-rRNA Processing from Cryo-Electron Microscopy

Findings

Concluding Remarks and Future Perspectives