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Nature Reviews. Cancer Jan 2018The ribosome is a complex molecular machine composed of numerous distinct proteins and nucleic acids and is responsible for protein synthesis in every living cell.... (Review)
Review
The ribosome is a complex molecular machine composed of numerous distinct proteins and nucleic acids and is responsible for protein synthesis in every living cell. Ribosome biogenesis is one of the most multifaceted and energy- demanding processes in biology, involving a large number of assembly and maturation factors, the functions of which are orchestrated by multiple cellular inputs, including mitogenic signals and nutrient availability. Although causal associations between inherited mutations affecting ribosome biogenesis and elevated cancer risk have been established over the past decade, mechanistic data have emerged suggesting a broader role for dysregulated ribosome biogenesis in the development and progression of most spontaneous cancers. In this Opinion article, we highlight the most recent findings that provide new insights into the molecular basis of ribosome biogenesis in cancer and offer our perspective on how these observations present opportunities for the design of new targeted cancer treatments.
Topics: Animals; Cell Proliferation; Humans; Neoplasms; Protein Biosynthesis; Ribosomal Proteins; Ribosomes; Signal Transduction
PubMed: 29192214
DOI: 10.1038/nrc.2017.104 -
Molecular Cell Apr 2022Ribosome-associated quality-control (RQC) surveys incomplete nascent polypeptides produced by interrupted translation. Central players in RQC are the human ribosome- and... (Review)
Review
Ribosome-associated quality-control (RQC) surveys incomplete nascent polypeptides produced by interrupted translation. Central players in RQC are the human ribosome- and tRNA-binding protein, NEMF, and its orthologs, yeast Rqc2 and bacterial RqcH, which sense large ribosomal subunits obstructed with nascent chains and then promote nascent-chain proteolysis. In canonical eukaryotic RQC, NEMF stabilizes the LTN1/Listerin E3 ligase binding to obstructed ribosomal subunits for nascent-chain ubiquitylation. Furthermore, NEMF orthologs across evolution modify nascent chains by mediating C-terminal, untemplated polypeptide elongation. In eukaryotes, this process exposes ribosome-buried nascent-chain lysines, the ubiquitin acceptor sites, to LTN1. Remarkably, in both bacteria and eukaryotes, C-terminal tails also have an extra-ribosomal function as degrons. Here, we discuss recent findings on RQC mechanisms and briefly review how ribosomal stalling is sensed upstream of RQC, including via ribosome collisions, from an evolutionary perspective. Because RQC defects impair cellular fitness and cause neurodegeneration, this knowledge provides a framework for pathway-related biology and disease studies.
Topics: Bacteria; Humans; Peptides; Protein Biosynthesis; Ribosomes; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 35452614
DOI: 10.1016/j.molcel.2022.03.038 -
Cancer Research Jul 2022Ribosomes are a complex ensemble of rRNA and ribosomal proteins that function as mRNA translation machines. Ribosome biogenesis is a multistep process that begins in the... (Review)
Review
Ribosomes are a complex ensemble of rRNA and ribosomal proteins that function as mRNA translation machines. Ribosome biogenesis is a multistep process that begins in the nucleolus and concludes in the cytoplasm. The process is tightly controlled by multiple checkpoint and surveillance pathways. Perturbations in these checkpoints and pathways can lead to hyperactivation of ribosome biogenesis. Emerging evidence suggests that cancer cells harbor a specialized class of ribosomes (onco-ribosomes) that facilitates the oncogenic translation program, modulates cellular functions, and promotes metabolic rewiring. Mutations in ribosomal proteins, rRNA processing, and ribosome assembly factors result in ribosomopathies that are associated with an increased risk of developing malignancies. Recent studies have linked mutations in ribosomal proteins and aberrant ribosomes with poor prognosis, highlighting ribosome-targeted therapy as a promising approach for treating patients with cancer. Here, we summarize various aspects of dysregulation of ribosome biogenesis and the impact of resultant onco-ribosomes on malignant tumor behavior, therapeutic resistance, and clinical outcome. Ribosome biogenesis is a promising therapeutic target, and understanding the important determinants of this process will allow for improved and perhaps selective therapeutic strategies to target ribosome biosynthesis.
Topics: Cell Nucleolus; Drug Resistance, Neoplasm; Humans; Neoplasm Metastasis; Neoplasms; RNA, Ribosomal; Ribosomal Proteins; Ribosomes
PubMed: 35303060
DOI: 10.1158/0008-5472.CAN-21-4087 -
Molecular Cell Aug 2018The ribosome has recently transitioned from being viewed as a passive, indiscriminate machine to a more dynamic macromolecular complex with specialized roles in the... (Review)
Review
The ribosome has recently transitioned from being viewed as a passive, indiscriminate machine to a more dynamic macromolecular complex with specialized roles in the cell. Here, we discuss the historical milestones from the discovery of the ribosome itself to how this ancient machinery has gained newfound appreciation as a more regulatory participant in the central dogma of gene expression. The first emerging examples of direct changes in ribosome composition at the RNA and protein level, coupled with an increased awareness of the role individual ribosomal components play in the translation of specific mRNAs, is opening a new field of study centered on ribosome-mediated control of gene regulation. In this Perspective, we discuss our current understanding of the known functions for ribosome heterogeneity, including specialized translation of individual transcripts, and its implications for the regulation and expression of key gene regulatory networks. In addition, we suggest what the crucial next steps are to ascertain the extent of ribosome heterogeneity and specialization and its importance for regulation of the proteome within subcellular space, across different cell types, and during multi-cellular organismal development.
Topics: Animals; Gene Expression Regulation; Gene Regulatory Networks; Humans; Internal Ribosome Entry Sites; Protein Biosynthesis; RNA; RNA, Messenger; Ribosomal Proteins; Ribosomes
PubMed: 30075139
DOI: 10.1016/j.molcel.2018.07.018 -
Molecular Cell May 2023Because of the central role ribosomes play for protein translation and ribosome-mediated mRNA and protein quality control (RQC), the ribosome pool is surveyed and...
Because of the central role ribosomes play for protein translation and ribosome-mediated mRNA and protein quality control (RQC), the ribosome pool is surveyed and dysfunctional ribosomes degraded both during assembly, as well as the functional cycle. Oxidative stress downregulates translation and damages mRNAs and ribosomal proteins (RPs). Although damaged mRNAs are detected and degraded via RQC, how cells mitigate damage to RPs is not known. Here, we show that cysteines in Rps26 and Rpl10 are readily oxidized, rendering the proteins non-functional. Oxidized Rps26 and Rpl10 are released from ribosomes by their chaperones, Tsr2 and Sqt1, and the damaged ribosomes are subsequently repaired with newly made proteins. Ablation of this pathway impairs growth, which is exacerbated under oxidative stress. These findings reveal an unanticipated mechanism for chaperone-mediated ribosome repair, augment our understanding of ribosome quality control, and explain previous observations of protein exchange in ribosomes from dendrites, with broad implications for aging and health.
Topics: Ribosomes; Ribosomal Proteins; Molecular Chaperones; Oxidative Stress; Protein Biosynthesis
PubMed: 37086725
DOI: 10.1016/j.molcel.2023.03.030 -
Wiley Interdisciplinary Reviews. RNA May 2021Ribosomal protein genes are among the most highly expressed genes in most cell types. Their products are generally essential for ribosome synthesis, which is the... (Review)
Review
Ribosomal protein genes are among the most highly expressed genes in most cell types. Their products are generally essential for ribosome synthesis, which is the cornerstone for cell growth and proliferation. Many cellular resources are dedicated to producing ribosomal proteins and thus this process needs to be regulated in ways that carefully balance the supply of nascent ribosomal proteins with the demand for new ribosomes. Ribosomal protein genes have classically been viewed as a uniform interconnected regulon regulated in eukaryotic cells by target of rapamycin and protein kinase A pathway in response to changes in growth conditions and/or cellular status. However, recent literature depicts a more complex picture in which the amount of ribosomal proteins produced varies between genes in response to two overlapping regulatory circuits. The first includes the classical general ribosome-producing program and the second is a gene-specific feature responsible for fine-tuning the amount of ribosomal proteins produced from each individual ribosomal gene. Unlike the general pathway that is mainly controlled at the level of transcription and translation, this specific regulation of ribosomal protein genes is largely achieved through changes in pre-mRNA splicing efficiency and mRNA stability. By combining general and specific regulation, the cell can coordinate ribosome production, while allowing functional specialization and diversity. Here we review the many ways ribosomal protein genes are regulated, with special focus on the emerging role of posttranscriptional regulatory events in fine-tuning the expression of ribosomal protein genes and its role in controlling the potential variation in ribosome functions. This article is categorized under: Translation > Ribosome Biogenesis Translation > Ribosome Structure/Function Translation > Translation Regulation.
Topics: Eukaryotic Cells; Gene Expression Regulation; RNA Stability; Ribosomal Proteins; Ribosomes
PubMed: 33038057
DOI: 10.1002/wrna.1632 -
Nature Apr 2015Ribosomes are translational machineries that catalyse protein synthesis. Ribosome structures from various species are known at the atomic level, but obtaining the...
Ribosomes are translational machineries that catalyse protein synthesis. Ribosome structures from various species are known at the atomic level, but obtaining the structure of the human ribosome has remained a challenge; efforts to address this would be highly relevant with regard to human diseases. Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. It provides unprecedented insights into ribosomal RNA entities and amino acid side chains, notably of the transfer RNA binding sites and specific molecular interactions with the exit site tRNA. It reveals atomic details of the subunit interface, which is seen to remodel strongly upon rotational movements of the ribosomal subunits. Furthermore, the structure paves the way for analysing antibiotic side effects and diseases associated with deregulated protein synthesis.
Topics: Binding Sites; Cryoelectron Microscopy; Electrons; Humans; Models, Molecular; RNA, Ribosomal; RNA, Transfer; Ribosomal Proteins; Ribosome Subunits; Ribosomes
PubMed: 25901680
DOI: 10.1038/nature14427 -
Nature Oct 2022Translation is the fundamental process of protein synthesis and is catalysed by the ribosome in all living cells. Here we use advances in cryo-electron tomography and...
Translation is the fundamental process of protein synthesis and is catalysed by the ribosome in all living cells. Here we use advances in cryo-electron tomography and sub-tomogram analysis to visualize the structural dynamics of translation inside the bacterium Mycoplasma pneumoniae. To interpret the functional states in detail, we first obtain a high-resolution in-cell average map of all translating ribosomes and build an atomic model for the M. pneumoniae ribosome that reveals distinct extensions of ribosomal proteins. Classification then resolves 13 ribosome states that differ in their conformation and composition. These recapitulate major states that were previously resolved in vitro, and reflect intermediates during active translation. On the basis of these states, we animate translation elongation inside native cells and show how antibiotics reshape the cellular translation landscapes. During translation elongation, ribosomes often assemble in defined three-dimensional arrangements to form polysomes. By mapping the intracellular organization of translating ribosomes, we show that their association into polysomes involves a local coordination mechanism that is mediated by the ribosomal protein L9. We propose that an extended conformation of L9 within polysomes mitigates collisions to facilitate translation fidelity. Our work thus demonstrates the feasibility of visualizing molecular processes at atomic detail inside cells.
Topics: Anti-Bacterial Agents; Cryoelectron Microscopy; Mycoplasma pneumoniae; Peptide Chain Elongation, Translational; Polyribosomes; Protein Biosynthesis; Ribosomal Proteins; Ribosomes
PubMed: 36171285
DOI: 10.1038/s41586-022-05255-2 -
Cell May 2023Ribosome production is vital for every cell, and failure causes human diseases. It is driven by ∼200 assembly factors functioning along an ordered pathway from the...
Ribosome production is vital for every cell, and failure causes human diseases. It is driven by ∼200 assembly factors functioning along an ordered pathway from the nucleolus to the cytoplasm. Structural snapshots of biogenesis intermediates from the earliest 90S pre-ribosomes to mature 40S subunits unravel the mechanisms of small ribosome synthesis. To view this SnapShot, open or download the PDF.
Topics: Humans; Cell Nucleolus; Eukaryotic Cells; Ribosomal Proteins; Ribosome Subunits, Small, Eukaryotic; Ribosomes
PubMed: 37172570
DOI: 10.1016/j.cell.2023.04.030 -
Cell Jun 2017During eukaryotic evolution, ribosomes have considerably increased in size, forming a surface-exposed ribosomal RNA (rRNA) shell of unknown function, which may create an...
During eukaryotic evolution, ribosomes have considerably increased in size, forming a surface-exposed ribosomal RNA (rRNA) shell of unknown function, which may create an interface for yet uncharacterized interacting proteins. To investigate such protein interactions, we establish a ribosome affinity purification method that unexpectedly identifies hundreds of ribosome-associated proteins (RAPs) from categories including metabolism and cell cycle, as well as RNA- and protein-modifying enzymes that functionally diversify mammalian ribosomes. By further characterizing RAPs, we discover the presence of ufmylation, a metazoan-specific post-translational modification (PTM), on ribosomes and define its direct substrates. Moreover, we show that the metabolic enzyme, pyruvate kinase muscle (PKM), interacts with sub-pools of endoplasmic reticulum (ER)-associated ribosomes, exerting a non-canonical function as an RNA-binding protein in the translation of ER-destined mRNAs. Therefore, RAPs interconnect one of life's most ancient molecular machines with diverse cellular processes, providing an additional layer of regulatory potential to protein expression.
Topics: Animals; Carrier Proteins; Embryonic Stem Cells; Endoplasmic Reticulum; Mass Spectrometry; Membrane Proteins; Mice; Protein Biosynthesis; Protein Interaction Mapping; Protein Processing, Post-Translational; Ribosomal Proteins; Ribosomes; Thyroid Hormones; Ubiquitin-Protein Ligases; Thyroid Hormone-Binding Proteins
PubMed: 28575669
DOI: 10.1016/j.cell.2017.05.022