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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 -
Nature Reviews. Microbiology Jan 2014The ribosome is one of the main antibiotic targets in the bacterial cell. Crystal structures of naturally produced antibiotics and their semi-synthetic derivatives bound... (Review)
Review
The ribosome is one of the main antibiotic targets in the bacterial cell. Crystal structures of naturally produced antibiotics and their semi-synthetic derivatives bound to ribosomal particles have provided unparalleled insight into their mechanisms of action, and they are also facilitating the design of more effective antibiotics for targeting multidrug-resistant bacteria. In this Review, I discuss the recent structural insights into the mechanism of action of ribosome-targeting antibiotics and the molecular mechanisms of bacterial resistance, in addition to the approaches that are being pursued for the production of improved drugs that inhibit bacterial protein synthesis.
Topics: Anti-Bacterial Agents; Bacteria; Bacterial Proteins; Drug Resistance, Bacterial; Protein Biosynthesis; Protein Conformation; Ribosomes
PubMed: 24336183
DOI: 10.1038/nrmicro3155 -
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 -
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 -
Trends in Biochemical Sciences Feb 2019The existence of eukaryotic ribosomes with distinct ribosomal protein (RP) stoichiometry and regulatory roles in protein synthesis has been speculated for over 60 years.... (Review)
Review
The existence of eukaryotic ribosomes with distinct ribosomal protein (RP) stoichiometry and regulatory roles in protein synthesis has been speculated for over 60 years. Recent advances in mass spectrometry (MS) and high-throughput analysis have begun to identify and characterize distinct ribosome stoichiometry in yeast and mammalian systems. In addition to RP stoichiometry, ribosomes host a vast array of protein modifications, effectively expanding the number of human RPs from 80 to many thousands of distinct proteoforms. Is it possible that these proteoforms combine to function as a 'ribosome code' to tune protein synthesis? We outline the specific benefits that translational regulation by specialized ribosomes can offer and discuss the means and methodologies available to correlate and characterize RP stoichiometry with function. We highlight previous research with a focus on formulating hypotheses that can guide future experiments and crack the ribosome code.
Topics: Animals; High-Throughput Screening Assays; Humans; Mass Spectrometry; Ribosomal Proteins; Ribosomes; Saccharomyces cerevisiae
PubMed: 30473427
DOI: 10.1016/j.tibs.2018.10.009 -
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 -
Biochemical Pharmacology Jan 2019Ribosomes are nanomachines essential for protein production in all living cells. Ribosome synthesis increases in cancer cells to cope with a rise in protein synthesis... (Review)
Review
Ribosomes are nanomachines essential for protein production in all living cells. Ribosome synthesis increases in cancer cells to cope with a rise in protein synthesis and sustain unrestricted growth. This increase in ribosome biogenesis is reflected by severe morphological alterations of the nucleolus, the cell compartment where the initial steps of ribosome biogenesis take place. Ribosome biogenesis has recently emerged as an effective target in cancer therapy, and several compounds that inhibit ribosome production or function, killing preferentially cancer cells, have entered clinical trials. Recent research indicates that cells express heterogeneous populations of ribosomes and that the composition of ribosomes may play a key role in tumorigenesis, exposing novel therapeutic opportunities. Here, we review recent data demonstrating that ribosome biogenesis is a promising druggable pathway in cancer therapy, and discuss future research perspectives.
Topics: Antineoplastic Agents; Humans; Molecular Targeted Therapy; Neoplasms; RNA, Ribosomal; Ribosomes
PubMed: 30468711
DOI: 10.1016/j.bcp.2018.11.014 -
Sub-cellular Biochemistry 2019Ribosomes are biological nanomachine that synthesise all proteins within a cell. It took decades to reveal the architecture of this essential cellular component. To... (Review)
Review
Ribosomes are biological nanomachine that synthesise all proteins within a cell. It took decades to reveal the architecture of this essential cellular component. To understand the structure -function relationship of this nanomachine needed the utilisisation of different biochemical, biophysical and structural techniques. Structural studies combined with mutagenesis of the different ribosomal complexes comprising various RNAs and proteins enabled us to understand how this machine works inside a cell. Nowadays quite a number of ribosomal structures were published that confirmed biochemical studies on particular steps of protein synthesis by the ribosome . Four major steps were identified: initiation , elongation, termination and recycling. These steps lead us to the important question how the ribosome function can be regulated. Advances in technology for cryo electron microscopy: sample preparations, image recording, developments in algorithms for image analysis and processing significantly helped in revelation of structural details of the ribosome . We now have a library of ribosome structures from prokaryotes to eukaryotes that enable us to understand the complex mechanics of this nanomachine. As this structural library continues to grow, we gradually improve our understanding of this process and how it can be regulated and how the specific ribosomes can be stalled or activated, or completely disabled. This article provides a comprehensive overview of ribosomal structures that represent structural snapshots of the ribosome at its different functional states. Better understanding rises more particular questions that have to be addressed by determination structures of more complexes.Synopsis: Structural biology of the ribosome.
Topics: Cryoelectron Microscopy; Protein Biosynthesis; Ribosomes
PubMed: 31939149
DOI: 10.1007/978-3-030-28151-9_3 -
Trends in Biochemical Sciences Jan 2022The conceptual origins of ribosome specialization can be traced back to the earliest days of molecular biology. Yet, this field has only recently begun to gather... (Review)
Review
The conceptual origins of ribosome specialization can be traced back to the earliest days of molecular biology. Yet, this field has only recently begun to gather momentum, with numerous studies identifying distinct heterogeneous ribosome populations across multiple species and model systems. It is proposed that some of these compositionally distinct ribosomes may be functionally specialized and able to regulate the translation of specific mRNAs. Identification and functional characterization of specialized ribosomes has the potential to elucidate a novel layer of gene expression control, at the level of translation, where the ribosome itself is a key regulatory player. In this review, we discuss different sources of ribosome heterogeneity, evidence for ribosome specialization, and also the future directions of this exciting field.
Topics: Protein Biosynthesis; RNA, Messenger; RNA, Ribosomal; Ribosomal Proteins; Ribosomes
PubMed: 34312084
DOI: 10.1016/j.tibs.2021.07.001