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The Journal of Cell Biology Apr 2023The coordinated integration of ribosomal RNA and protein into two functional ribosomal subunits is safeguarded by quality control checkpoints that ensure ribosomes are... (Review)
Review
The coordinated integration of ribosomal RNA and protein into two functional ribosomal subunits is safeguarded by quality control checkpoints that ensure ribosomes are correctly assembled and functional before they engage in translation. Quality control is critical in maintaining the integrity of ribosomes and necessary to support healthy cell growth and prevent diseases associated with mistakes in ribosome assembly. Its importance is demonstrated by the finding that bypassing quality control leads to misassembled, malfunctioning ribosomes with altered translation fidelity, which change gene expression and disrupt protein homeostasis. In this review, we outline our understanding of quality control within ribosome synthesis and how failure to enforce quality control contributes to human disease. We first provide a definition of quality control to guide our investigation, briefly present the main assembly steps, and then examine stages of assembly that test ribosome function, establish a pass-fail system to evaluate these functions, and contribute to altered ribosome performance when bypassed, and are thus considered "quality control."
Topics: Humans; Ribosomal Proteins; Ribosomes; RNA, Ribosomal; Disease
PubMed: 36790396
DOI: 10.1083/jcb.202209115 -
Cold Spring Harbor Symposia on... 2009By translating genetically encoded information to synthesize proteins, the ribosome has a central and fundamental role in the molecular biology of the cell. Virtually... (Review)
Review
By translating genetically encoded information to synthesize proteins, the ribosome has a central and fundamental role in the molecular biology of the cell. Virtually every molecule made in every cell was made either directly by the ribosome or by enzymes made by the ribosome. Although the ribosome was discovered half a century ago, progress in the field of translation has been revolutionized by the atomic structures of the ribosomal subunits determined in 2000. These structures paved the way not only for more sophisticated biochemical and genetic experiments, but also for the phasing and/or molecular interpretation of all subsequent structures of the ribosome by crystallography or cryoEM (cryo-electron microscopy). In addition to facilitating our understanding of ribosome function, these structures also shed light on the evolution of the ribosome.
Topics: Evolution, Molecular; Models, Molecular; Molecular Structure; Protein Biosynthesis; RNA; Ribosomes
PubMed: 19955257
DOI: 10.1101/sqb.2009.74.032 -
Phytochemistry Oct 2022Ribosome inactivating proteins (RIPs) are rRNA N-glycosylases (EC 3.2.2.22) best known for hydrolyzing an adenine base from the conserved sarcin/ricin loop of ribosomal... (Review)
Review
Ribosome inactivating proteins (RIPs) are rRNA N-glycosylases (EC 3.2.2.22) best known for hydrolyzing an adenine base from the conserved sarcin/ricin loop of ribosomal RNA. Protein translation is inhibited by ribosome depurination; therefore, RIPs are generally considered toxic to cells. The expression of some RIPs is upregulated by biotic and abiotic stress, though the connection between RNA depurination and defense response is not well understood. Despite their prevalence in approximately one-third of flowering plant orders, our knowledge of RIPs stems primarily from biochemical analyses of individuals or genomics-scale analyses of small datasets from a limited number of species. Here, we performed an unbiased search for proteins with RIP domains and identified several-fold more RIPs than previously known - more than 800 from 120 species, many with novel associated domains and physicochemical characteristics. Based on protein domain configuration, we established 15 distinct groups, suggesting diverse functionality. Surprisingly, most of these RIPs lacked a signal peptide, indicating they may be localized to the nucleocytoplasm of cells, raising questions regarding their toxicity against conspecific ribosomes. Our phylogenetic analysis significantly extends previous models for RIP evolution in plants, predicting an original single-domain RIP that later evolved to acquire a signal peptide and different protein domains. We show that RIPs are distributed throughout 21 plant orders with many species maintaining genes for more than one RIP group. Our analyses provide the foundation for further characterization of these new RIP types, to understand how these enzymes function in plants.
Topics: Phylogeny; Plant Proteins; Protein Sorting Signals; RNA, Ribosomal; Ribosome Inactivating Proteins; Ribosomes
PubMed: 35934106
DOI: 10.1016/j.phytochem.2022.113337 -
International Journal of Molecular... Apr 2020The synthesis of ribosomes is one of the central and most resource demanding processes in each living cell. As ribosome biogenesis is tightly linked with the regulation... (Review)
Review
The synthesis of ribosomes is one of the central and most resource demanding processes in each living cell. As ribosome biogenesis is tightly linked with the regulation of the cell cycle, perturbation of ribosome formation can trigger severe diseases, including cancer. Eukaryotic ribosome biogenesis starts in the nucleolus with pre-rRNA transcription and the initial assembly steps, continues in the nucleoplasm and is finished in the cytoplasm. From start to end, this process is highly dynamic and finished within few minutes. Despite the tremendous progress made during the last decade, the coordination of the individual maturation steps is hard to unravel by a conventional methodology. In recent years small molecular compounds were identified that specifically block either rDNA transcription or distinct steps within the maturation pathway. As these inhibitors diffuse into the cell rapidly and block their target proteins within seconds, they represent excellent tools to investigate ribosome biogenesis. Here we review how the inhibitors affect ribosome biogenesis and discuss how these effects can be interpreted by taking the complex self-regulatory mechanisms of the pathway into account. With this we want to highlight the potential of low molecular weight inhibitors to approach the dynamic nature of the ribosome biogenesis pathway.
Topics: Animals; Drug Discovery; Gene Expression Regulation; Humans; Molecular Probes; Protein Binding; Protein Biosynthesis; RNA, Ribosomal; Ribosomal Proteins; Ribosomes
PubMed: 32340379
DOI: 10.3390/ijms21082998 -
International Review of Cell and... 2010In this chapter we describe the status of the research concerning the nucleolus, the major nuclear body. The nucleolus has been recognized as a dynamic organelle with... (Review)
Review
In this chapter we describe the status of the research concerning the nucleolus, the major nuclear body. The nucleolus has been recognized as a dynamic organelle with many more functions than one could imagine. In fact, in addition to its fundamental role in the biogenesis of preribosomes, the nucleolus takes part in many other cellular processes and functions, such as the cell-cycle control and the p53 pathway: the direct or indirect involvement of the nucleolus in these various processes makes it sensitive to their alteration. Moreover, it is worth noting that the different nucleolar factors participating to independent mechanisms show different dynamics of association/disassociation with the nucleolar body.
Topics: Animals; Cell Nucleolus; Humans; Ribosomal Proteins; Ribosomes; Signal Transduction
PubMed: 20875629
DOI: 10.1016/S1937-6448(10)84002-X -
Experimental Cell Research May 2004The synthesis of ribosomes in eukaryotes involves processing of pre-ribosomal RNA (pre-rRNA) and sequential assembly of a large number of ribosomal proteins on the... (Review)
Review
The synthesis of ribosomes in eukaryotes involves processing of pre-ribosomal RNA (pre-rRNA) and sequential assembly of a large number of ribosomal proteins on the rRNAs. Although we have gained tremendous insights into the processing of pre-rRNA intermediates in the last three decades, little was known about the dynamic nature of ribosome biogenesis. Only recently the development of efficient affinity-purification procedures and mass-spectrometry techniques has allowed the isolation of large pre-ribosomal complexes, which led to the identification of several ribosome assembly intermediates and a large number of novel ribosome assembly factors. In this mini-review, we summarize some of the discoveries that have been made in the field of ribosome biogenesis in the past 30 years and highlight some key aspects about what remains to be learned.
Topics: Macromolecular Substances; Nuclear Proteins; RNA Precursors; Ribosomal Proteins; Ribosomes; Yeasts
PubMed: 15120992
DOI: 10.1016/j.yexcr.2004.03.016 -
FEBS Letters Mar 2002General principles of structure and function of the ribosome are surveyed, and the translating ribosome is regarded as a molecular conveying machine. Two coupled... (Review)
Review
General principles of structure and function of the ribosome are surveyed, and the translating ribosome is regarded as a molecular conveying machine. Two coupled conveying processes, the passing of compact tRNA globules and the drawing of linear mRNA chain through intraribosomal channel, are considered driven by discrete acts of translocation during translation. Instead of mechanical transmission mechanisms and power-stroke 'motors', thermal motion and chemically induced changes in affinities of ribosomal binding sites for their ligands (tRNAs, mRNA, elongation factors) are proposed to underlie all the directional movements within the ribosomal complex. The GTP-dependent catalysis of conformational transitions by elongation factors during translation is also discussed.
Topics: Animals; Biological Transport; Guanosine Triphosphate; Humans; Models, Molecular; Peptide Elongation Factors; Protein Biosynthesis; Protein Conformation; Ribosomes
PubMed: 11904172
DOI: 10.1016/s0014-5793(02)02309-8 -
Cells Mar 2020The human 80S ribosome is the cellular nucleoprotein nanomachine in charge of protein synthesis that is profoundly affected during cancer transformation by oncogenic... (Review)
Review
The human 80S ribosome is the cellular nucleoprotein nanomachine in charge of protein synthesis that is profoundly affected during cancer transformation by oncogenic proteins and provides cancerous proliferating cells with proteins and therefore biomass. Indeed, cancer is associated with an increase in ribosome biogenesis and mutations in several ribosomal proteins genes are found in ribosomopathies, which are congenital diseases that display an elevated risk of cancer. Ribosomes and their biogenesis therefore represent attractive anti-cancer targets and several strategies are being developed to identify efficient and specific drugs. Homoharringtonine (HHT) is the only direct ribosome inhibitor currently used in clinics for cancer treatments, although many classical chemotherapeutic drugs also appear to impact on protein synthesis. Here we review the role of the human ribosome as a medical target in cancer, and how functional and structural analysis combined with chemical synthesis of new inhibitors can synergize. The possible existence of oncoribosomes is also discussed. The emerging idea is that targeting the human ribosome could not only allow the interference with cancer cell addiction towards protein synthesis and possibly induce their death but may also be highly valuable to decrease the levels of oncogenic proteins that display a high turnover rate (MYC, MCL1). Cryo-electron microscopy (cryo-EM) is an advanced method that allows the visualization of human ribosome complexes with factors and bound inhibitors to improve our understanding of their functioning mechanisms mode. Cryo-EM structures could greatly assist the foundation phase of a novel drug-design strategy. One goal would be to identify new specific and active molecules targeting the ribosome in cancer such as derivatives of cycloheximide, a well-known ribosome inhibitor.
Topics: Cryoelectron Microscopy; Drug Design; Humans; Models, Molecular; Neoplasms; Protein Biosynthesis; Ribosomes
PubMed: 32151059
DOI: 10.3390/cells9030629 -
Current Opinion in Microbiology Apr 2013Translation of the mRNA-encoded genetic information into proteins is catalyzed by the intricate ribonucleoprotein machine, the ribosome. Historically, the bacterial... (Review)
Review
Translation of the mRNA-encoded genetic information into proteins is catalyzed by the intricate ribonucleoprotein machine, the ribosome. Historically, the bacterial ribosome is viewed as an unchangeable entity, constantly equipped with the entire complement of RNAs and proteins. Conversely, several lines of evidence indicate the presence of functional selective ribosomal subpopulations that exhibit variations in the RNA or the protein components and modulate the translational program in response to environmental changes. Here, we summarize these findings, which raise the functional status of the ribosome from a protein synthesis machinery only to a regulatory hub that integrates environmental cues in the process of protein synthesis, thereby adding an additional level of complexity to the regulation of gene expression.
Topics: Bacteria; Gene Expression Regulation, Bacterial; Genetic Variation; Protein Biosynthesis; Ribosomes
PubMed: 23415603
DOI: 10.1016/j.mib.2013.01.009 -
International Journal of Molecular... Jun 2019In the past few decades, studies on translation have converged towards the metaphor of a "ribosome nanomachine"; they also revealed intriguing ribosome properties... (Review)
Review
In the past few decades, studies on translation have converged towards the metaphor of a "ribosome nanomachine"; they also revealed intriguing ribosome properties challenging this view. Many studies have shown that to perform an accurate protein synthesis in a fluctuating cellular environment, ribosomes sense, transfer information and even make decisions. This complex "behaviour" that goes far beyond the skills of a simple mechanical machine has suggested that the ribosomal protein networks could play a role equivalent to nervous circuits at a molecular scale to enable information transfer and processing during translation. We analyse here the significance of this analogy and establish a preliminary link between two fields: ribosome structure-function studies and the analysis of information processing systems. This cross-disciplinary analysis opens new perspectives about the mechanisms of information transfer and processing in ribosomes and may provide new conceptual frameworks for the understanding of the behaviours of unicellular organisms.
Topics: Animals; Humans; Neural Networks, Computer; Ribosomes; Signal Transduction
PubMed: 31207893
DOI: 10.3390/ijms20122911