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Cells Sep 2020Ribosomopathies are a group of rare diseases in which genetic mutations cause defects in either ribosome biogenesis or function, given specific phenotypes. Ribosomal... (Review)
Review
Ribosomopathies are a group of rare diseases in which genetic mutations cause defects in either ribosome biogenesis or function, given specific phenotypes. Ribosomal proteins, and multiple other factors that are necessary for ribosome biogenesis (rRNA processing, assembly of subunits, export to cytoplasm), can be affected in ribosomopathies. Despite the need for ribosomes in all cell types, these diseases result mainly in tissue-specific impairments. Depending on the type of ribosomopathy and its pathogenicity, there are many potential therapeutic targets. The present manuscript will review our knowledge of ribosomopathies, discuss current treatments, and introduce the new therapeutic perspectives based on recent research. Diamond-Blackfan anemia, currently treated with blood transfusion prior to steroids, could be managed with a range of new compounds, acting mainly on anemia, such as L-leucine. Treacher Collins syndrome could be managed by various treatments, but it has recently been shown that proteasomal inhibition by MG132 or Bortezomib may improve cranial skeleton malformations. Developmental defects resulting from ribosomopathies could be also treated pharmacologically after birth. It might thus be possible to treat certain ribosomopathies without using multiple treatments such as surgery and transplants. Ribosomopathies remain an open field in the search for new therapeutic approaches based on our recent understanding of the role of ribosomes and progress in gene therapy for curing genetic disorders.
Topics: Anemia, Diamond-Blackfan; Humans; Ribosomal Proteins; Ribosomes
PubMed: 32932838
DOI: 10.3390/cells9092080 -
Molecular Cell Feb 2023mRNA translation is a highly conserved and tightly controlled mechanism for protein synthesis and is well known to be altered by oncogenes to promote cancer development.... (Review)
Review
mRNA translation is a highly conserved and tightly controlled mechanism for protein synthesis and is well known to be altered by oncogenes to promote cancer development. This distorted mRNA translation is accompanied by the vulnerability of cancer to inhibitors of key mRNA translation components. Novel studies also suggest that these alternations could be utilized for immunotherapy. Ribosome heterogeneity and alternative responses to nutrient shortages, which aid cancer growth and spread, are proposed to elicit aberrant protein production but may also result in previously unidentified therapeutic targets, such as the presentation of cancer-specific peptides at the surface of cancer cells (neoepitopes). This review will assess the driving forces in tRNA and ribosome function that underlie proteome diversification due to alterations in mRNA translation in cancer cells.
Topics: Proteome; Protein Biosynthesis; Ribosomes; Peptides; RNA, Transfer; Neoplasms
PubMed: 36521491
DOI: 10.1016/j.molcel.2022.11.014 -
Genes Mar 2021Ribosome biogenesis is a complex process that is responsible for the formation of ribosomes and ultimately global protein synthesis. The first step in this process is... (Review)
Review
Ribosome biogenesis is a complex process that is responsible for the formation of ribosomes and ultimately global protein synthesis. The first step in this process is the synthesis of the ribosomal RNA in the nucleolus, transcribed by RNA Polymerase I. Historically, abnormal nucleolar structure is indicative of poor cancer prognoses. In recent years, it has been shown that ribosome biogenesis, and rDNA transcription in particular, is dysregulated in cancer cells. Coupled with advancements in screening technology that allowed for the discovery of novel drugs targeting RNA Polymerase I, this transcriptional machinery is an increasingly viable target for cancer therapies. In this review, we discuss ribosome biogenesis in breast cancer and the different cellular pathways involved. Moreover, we discuss current therapeutics that have been found to affect rDNA transcription and more novel drugs that target rDNA transcription machinery as a promising avenue for breast cancer treatment.
Topics: Breast Neoplasms; DNA, Ribosomal; Female; Gene Expression Regulation; Humans; RNA, Ribosomal; Ribosomes; Transcription, Genetic
PubMed: 33805424
DOI: 10.3390/genes12040502 -
ACS Synthetic Biology Nov 2017Biocontainment systems are crucial for preventing genetically modified organisms from escaping into natural ecosystems. Here, we describe the orthogonal ribosome...
Biocontainment systems are crucial for preventing genetically modified organisms from escaping into natural ecosystems. Here, we describe the orthogonal ribosome biofirewall, which consists of an activation circuit and a degradation circuit. The activation circuit is a genetic AND gate based on activation of the encrypted pathway by the orthogonal ribosome in response to specific environmental signals. The degradation circuit is a genetic NOT gate with an output of I-SceI homing endonuclease, which conditionally degrades the orthogonal ribosome genes. We demonstrate that the activation circuit can be flexibly incorporated into genetic circuits and metabolic pathways for encryption. The plasmid-based encryption of the deoxychromoviridans pathway and the genome-based encryption of lacZ are tightly regulated and can decrease the expression to 7.3% and 7.8%, respectively. We validated the ability of the degradation circuit to decrease the expression levels of the target plasmids and the orthogonal rRNA (O-rRNA) plasmids to 0.8% in lab medium and 0.76% in nonsterile soil medium, respectively. Our orthogonal ribosome biofirewall is a versatile platform that can be useful in biosafety research and in the biotechnology industry.
Topics: Escherichia coli; Lac Operon; RNA, Bacterial; RNA, Ribosomal; Ribosomes
PubMed: 28783349
DOI: 10.1021/acssynbio.7b00148 -
Philosophical Transactions of the Royal... Mar 2017Bacterial ribosome biogenesis has been an active area of research for more than 30 years and has served as a test-bed for the development of new biochemical, biophysical... (Review)
Review
Bacterial ribosome biogenesis has been an active area of research for more than 30 years and has served as a test-bed for the development of new biochemical, biophysical and structural techniques to understand macromolecular assembly generally. Recent work inspecting the process in vivo has advanced our understanding of the role of ribosome biogenesis factors, the co-transcriptional nature of assembly, the kinetics of the process under sub-optimal conditions, and the rRNA folding and ribosome protein binding pathways. Additionally, new structural work enabled by single-particle electron microscopy has helped to connect in vitro ribosomal protein binding maps to the underlying RNA. This review summarizes the state of these in vivo studies, provides a kinetic model for ribosome assembly under sub-optimal conditions, and describes a framework to compare newly emerging assembly intermediate structures.This article is part of the themed issue 'Perspectives on the ribosome'.
Topics: Bacterial Physiological Phenomena; Organelle Biogenesis; RNA, Bacterial; RNA, Ribosomal; Ribosomes
PubMed: 28138067
DOI: 10.1098/rstb.2016.0181 -
Biochemical Society Transactions Aug 2018The control of translation is increasingly recognized as a major factor in determining protein levels in the cell. The ribosome - the cellular machine that mediates... (Review)
Review
The control of translation is increasingly recognized as a major factor in determining protein levels in the cell. The ribosome - the cellular machine that mediates protein synthesis - is typically seen as a key, but invariant, player in this process. This is because translational control is thought to be mediated by other auxiliary factors while ribosome recruitment is seen as the end-point of regulation. However, recent developments have made it clear that heterogeneous ribosome types can exist in different tissues, and more importantly, that these ribosomes can preferentially translate different subsets of mRNAs. In so doing, heterogeneous ribosomes could be key regulatory players in differentiation and development. Here, we examine current evidence for the existence of different ribosome types and how they might arise. In particular, we will take a close look at the mechanisms through which these ribosomes might mediate selective mRNA translation. We also summarize recently developed techniques/approaches that will aid in our understanding of the functions of such specialized ribosomes.
Topics: Humans; Protein Biosynthesis; Proteins; RNA, Messenger; RNA, Ribosomal; Ribosomal Proteins; Ribosomes
PubMed: 29986937
DOI: 10.1042/BST20160426 -
Biomolecules May 2023Ribosome assembly is one of the most fundamental processes of gene expression and has served as a playground for investigating the molecular mechanisms of how... (Review)
Review
Ribosome assembly is one of the most fundamental processes of gene expression and has served as a playground for investigating the molecular mechanisms of how protein-RNA complexes (RNPs) assemble. A bacterial ribosome is composed of around 50 ribosomal proteins, several of which are co-transcriptionally assembled on a ~4500-nucleotide-long pre-rRNA transcript that is further processed and modified during transcription, the entire process taking around 2 min in vivo and being assisted by dozens of assembly factors. How this complex molecular process works so efficiently to produce an active ribosome has been investigated over decades, resulting in the development of a plethora of novel approaches that can also be used to study the assembly of other RNPs in prokaryotes and eukaryotes. Here, we review biochemical, structural, and biophysical methods that have been developed and integrated to provide a detailed and quantitative understanding of the complex and intricate molecular process of bacterial ribosome assembly. We also discuss emerging, cutting-edge approaches that could be used in the future to study how transcription, rRNA processing, cellular factors, and the native cellular environment shape ribosome assembly and RNP assembly at large.
Topics: Ribosomes; Ribosomal Proteins; Ribonucleoproteins; RNA
PubMed: 37238735
DOI: 10.3390/biom13050866 -
Biochemistry. Biokhimiia Nov 2020In response to stress, eubacteria reduce the level of protein synthesis and either disassemble ribosomes into the 30S and 50S subunits or turn them into translationally... (Review)
Review
In response to stress, eubacteria reduce the level of protein synthesis and either disassemble ribosomes into the 30S and 50S subunits or turn them into translationally inactive 70S and 100S complexes. This helps the cell to solve two principal tasks: (i) to reduce the cost of protein biosynthesis under unfavorable conditions, and (ii) to preserve functional ribosomes for rapid recovery of protein synthesis until favorable conditions are restored. All known genes for ribosome silencing factors and hibernation proteins are located in the operons associated with the response to starvation as one of the stress factors, which helps the cells to coordinate the slowdown of protein synthesis with the overall stress response. It is possible that hibernation systems work as regulators that coordinate the intensity of protein synthesis with the energy state of bacterial cell. Taking into account the limited amount of nutrients in natural conditions and constant pressure of other stress factors, bacterial ribosome should remain most of time in a complex with the silencing/hibernation proteins. Therefore, hibernation is an additional stage between the ribosome recycling and translation initiation, at which the ribosome is maintained in a "preserved" state in the form of separate subunits, non-translating 70S particles, or 100S dimers. The evolution of the ribosome hibernation has occurred within a very long period of time; ribosome hibernation is a conserved mechanism that is essential for maintaining the energy- and resource-consuming process of protein biosynthesis in organisms living in changing environment under stress conditions.
Topics: Bacteria; Protein Biosynthesis; Ribosomal Proteins; Ribosomes
PubMed: 33280583
DOI: 10.1134/S0006297920110115 -
Trends in Plant Science Nov 2015The biogenesis of eukaryotic ribosomes is a fundamental process involving hundreds of ribosome biogenesis factors (RBFs) in three compartments of the cell, namely the... (Review)
Review
The biogenesis of eukaryotic ribosomes is a fundamental process involving hundreds of ribosome biogenesis factors (RBFs) in three compartments of the cell, namely the nucleolus, nucleus, and cytoplasm. Many RBFs are involved in the processing of the primary ribosomal (r)RNA transcript, in which three of the four rRNAs are imbedded. While pre-rRNA processing is well described for yeast and mammals, a detailed processing scheme for plants is lacking. Here, we discuss the emerging scheme of pre-rRNA processing in Arabidopsis thaliana in comparison to other eukaryotes, with a focus on plant characteristics. In addition, we highlight the impact of the ribosome and its biogenesis on developmental processes because common phenotypes can be observed for ribosomal protein and RBF mutants.
Topics: Arabidopsis; Organelle Biogenesis; RNA Precursors; RNA, Plant; Ribosomal Proteins; Ribosomes
PubMed: 26459664
DOI: 10.1016/j.tplants.2015.07.003 -
Science (New York, N.Y.) Nov 2017Ribosomopathies are a group of human disorders most commonly caused by ribosomal protein haploinsufficiency or defects in ribosome biogenesis. These conditions manifest... (Review)
Review
Ribosomopathies are a group of human disorders most commonly caused by ribosomal protein haploinsufficiency or defects in ribosome biogenesis. These conditions manifest themselves as physiological defects in specific cell and tissue types. We review current molecular models to explain ribosomopathies and attempt to reconcile the tissue specificity of these disorders with the ubiquitous requirement for ribosomes in all cells. Ribosomopathies as a group are diverse in their origins and clinical manifestations; we use the well-described Diamond-Blackfan anemia (DBA) as a specific example to highlight some common features. We discuss ribosome homeostasis as an overarching principle that governs the sensitivity of specific cells and tissue types to ribosomal protein mutations. Mathematical models and experimental insights rationalize how even subtle shifts in the availability of ribosomes, such as those created by ribosome haploinsufficiency, can drive messenger RNA-specific effects on protein expression. We discuss recently identified roles played by ribosome rescue and recycling factors in regulating ribosome homeostasis.
Topics: Anemia, Diamond-Blackfan; Cell Cycle Checkpoints; Haploinsufficiency; Homeostasis; Humans; Models, Biological; Organ Specificity; Protein Biosynthesis; Ribosomal Proteins; Ribosomes; Tumor Suppressor Protein p53
PubMed: 29097519
DOI: 10.1126/science.aan2755