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Wiley Interdisciplinary Reviews. RNA Sep 2016During protein synthesis, tRNA and mRNA are translocated from the A to P to E sites of the ribosome thus enabling the ribosome to translate one codon of mRNA after the... (Review)
Review
During protein synthesis, tRNA and mRNA are translocated from the A to P to E sites of the ribosome thus enabling the ribosome to translate one codon of mRNA after the other. Ribosome translocation along mRNA is induced by the universally conserved ribosome GTPase, elongation factor G (EF-G) in bacteria and elongation factor 2 (EF-2) in eukaryotes. Recent structural and single-molecule studies revealed that tRNA and mRNA translocation within the ribosome is accompanied by cyclic forward and reverse rotations between the large and small ribosomal subunits parallel to the plane of the intersubunit interface. In addition, during ribosome translocation, the 'head' domain of small ribosomal subunit undergoes forward- and back-swiveling motions relative to the rest of the small ribosomal subunit around the axis that is orthogonal to the axis of intersubunit rotation. tRNA/mRNA translocation is also coupled to the docking of domain IV of EF-G into the A site of the small ribosomal subunit that converts the thermally driven motions of the ribosome and tRNA into the forward translocation of tRNA/mRNA inside the ribosome. Despite recent and enormous progress made in the understanding of the molecular mechanism of ribosome translocation, the sequence of structural rearrangements of the ribosome, EF-G and tRNA during translocation is still not fully established and awaits further investigation. WIREs RNA 2016, 7:620-636. doi: 10.1002/wrna.1354 For further resources related to this article, please visit the WIREs website.
Topics: Eukaryota; Peptide Elongation Factor 2; Peptide Elongation Factor G; Prokaryotic Cells; Protein Biosynthesis; RNA, Messenger; RNA, Transfer; Ribosomes
PubMed: 27117863
DOI: 10.1002/wrna.1354 -
Methods in Molecular Biology (Clifton,... 2022Ribosomes are universally conserved ribonucleoprotein complexes involved in the decoding of the genetic information contained in messenger RNAs into proteins.... (Review)
Review
Ribosomes are universally conserved ribonucleoprotein complexes involved in the decoding of the genetic information contained in messenger RNAs into proteins. Accordingly, ribosome biogenesis is a fundamental cellular process required for functional ribosome homeostasis and to preserve satisfactory gene expression capability.Although the ribosome is universally conserved, its biogenesis shows an intriguing degree of variability across the tree of life . These differences also raise yet unresolved questions. Among them are (a) what are, if existing, the remaining ancestral common principles of ribosome biogenesis ; (b) what are the molecular impacts of the evolution history and how did they contribute to (re)shape the ribosome biogenesis pathway across the tree of life ; (c) what is the extent of functional divergence and/or convergence (functional mimicry), and in the latter case (if existing) what is the molecular basis; (d) considering the universal ribosome conservation, what is the capability of functional plasticity and cellular adaptation of the ribosome biogenesis pathway?In this review, we provide a brief overview of ribosome biogenesis across the tree of life and try to illustrate some potential and/or emerging answers to these unresolved questions.
Topics: RNA, Messenger; RNA, Ribosomal; Ribosomes
PubMed: 35796979
DOI: 10.1007/978-1-0716-2501-9_1 -
Aging Apr 2019The biosynthesis of ribosomes is a complex process that requires the coordinated action of many factors and a huge energy investment from the cell. Ribosomes are... (Review)
Review
The biosynthesis of ribosomes is a complex process that requires the coordinated action of many factors and a huge energy investment from the cell. Ribosomes are essential for protein production, and thus for cellular survival, growth and proliferation. Ribosome biogenesis is initiated in the nucleolus and includes: the synthesis and processing of ribosomal RNAs, assembly of ribosomal proteins, transport to the cytoplasm and association of ribosomal subunits. The disruption of ribosome biogenesis at various steps, with either increased or decreased expression of different ribosomal components, can promote cell cycle arrest, senescence or apoptosis. Additionally, interference with ribosomal biogenesis is often associated with cancer, aging and age-related degenerative diseases. Here, we review current knowledge on impaired ribosome biogenesis, discuss the main factors involved in stress responses under such circumstances and focus on examples with clinical relevance.
Topics: Aging; Animals; Humans; Neoplasms; Organelle Biogenesis; Ribosomal Proteins; Ribosomes
PubMed: 31026227
DOI: 10.18632/aging.101922 -
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 -
The Journal of Cell Biology Jun 2020Translation control is critical to regulate protein expression. By directly adjusting protein levels, cells can quickly respond to dynamic transitions during stem cell... (Review)
Review
Translation control is critical to regulate protein expression. By directly adjusting protein levels, cells can quickly respond to dynamic transitions during stem cell differentiation and embryonic development. Ribosomes are multisubunit cellular assemblies that mediate translation. Previously seen as invariant machines with the same composition of components in all conditions, recent studies indicate that ribosomes are heterogeneous and that different ribosome types can preferentially translate specific subsets of mRNAs. Such heterogeneity and specialized translation functions are very important in stem cells and development, as they allow cells to quickly respond to stimuli through direct changes of protein abundance. In this review, we discuss ribosome heterogeneity that arises from multiple features of rRNAs, including rRNA variants and rRNA modifications, and ribosomal proteins, including their stoichiometry, compositions, paralogues, and posttranslational modifications. We also discuss alterations of ribosome-associated proteins (RAPs), with a particular focus on their consequent specialized translational control in stem cells and development.
Topics: Cell Differentiation; Growth and Development; Humans; Protein Biosynthesis; Protein Processing, Post-Translational; RNA, Messenger; RNA, Ribosomal; Ribosomal Proteins; Ribosomes; Stem Cells
PubMed: 32330234
DOI: 10.1083/jcb.202001108 -
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 -
RNA Biology Oct 2021Ribosomes are essential nanomachines responsible for all protein production in cells. Ribosome biogenesis and function are energy costly processes, they are tightly... (Review)
Review
Ribosomes are essential nanomachines responsible for all protein production in cells. Ribosome biogenesis and function are energy costly processes, they are tightly regulated to match cellular needs. In cancer, major pathways that control ribosome biogenesis and function are often deregulated to ensure cell survival and to accommodate the continuous proliferation of tumour cells. Ribosomal RNAs (rRNAs) are abundantly modified with 2'-O-methylation (Nm, ribomethylation) being one of the most common modifications. In eukaryotic ribosomes, ribomethylation is performed by the methyltransferase Fibrillarin guided by box C/D small nucleolar RNAs (snoRNAs). Accumulating evidences indicate that snoRNA expression and ribosome methylation profiles are altered in cancer. Here we review our current knowledge on differential snoRNA expression and rRNA 2'-O methylation in the context of human malignancies, and discuss the consequences and opportunities for cancer diagnostics, prognostics, and therapeutics.
Topics: Animals; Humans; Methylation; Neoplasms; RNA Processing, Post-Transcriptional; RNA, Ribosomal; RNA, Small Nucleolar; Ribosomes
PubMed: 34775914
DOI: 10.1080/15476286.2021.1991167 -
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 -
Wiley Interdisciplinary Reviews. RNA 2011The ribosome is a large complex containing both protein and RNA which must be assembled in a precise manner to allow proper functioning in the critical role of protein... (Review)
Review
The ribosome is a large complex containing both protein and RNA which must be assembled in a precise manner to allow proper functioning in the critical role of protein synthesis. 5S rRNA is the smallest of the RNA components of the ribosome, and although it has been studied for decades, we still do not have a clear understanding of its function within the complex ribosome machine. It is the only RNA species that binds ribosomal proteins prior to its assembly into the ribosome. Its transport into the nucleolus requires this interaction. Here we present an overview of some of the key findings concerning the structure and function of 5S rRNA and how its association with specific proteins impacts its localization and function.
Topics: Animals; Base Sequence; Cytoplasm; Humans; Mitochondria; Models, Biological; Models, Molecular; Nucleic Acid Conformation; RNA Processing, Post-Transcriptional; RNA, Ribosomal, 5S; RNA-Binding Proteins; Ribosomal Proteins; Ribosomes; Transcription Factor TFIIIA
PubMed: 21957041
DOI: 10.1002/wrna.74 -
Acta Crystallographica. Section D,... Jun 2017Protein folding, a process that underpins cellular activity, begins co-translationally on the ribosome. During translation, a newly synthesized polypeptide chain enters... (Review)
Review
Protein folding, a process that underpins cellular activity, begins co-translationally on the ribosome. During translation, a newly synthesized polypeptide chain enters the ribosomal exit tunnel and actively interacts with the ribosome elements - the r-proteins and rRNA that line the tunnel - prior to emerging into the cellular milieu. While understanding of the structure and function of the ribosome has advanced significantly, little is known about the process of folding of the emerging nascent chain (NC). Advances in cryo-electron microscopy are enabling visualization of NCs within the exit tunnel, allowing early glimpses of the interplay between the NC and the ribosome. Once it has emerged from the exit tunnel into the cytosol, the NC (still attached to its parent ribosome) can acquire a range of conformations, which can be characterized by NMR spectroscopy. Using experimental restraints within molecular-dynamics simulations, the ensemble of NC structures can be described. In order to delineate the process of co-translational protein folding, a hybrid structural biology approach is foreseeable, potentially offering a complete atomic description of protein folding as it occurs on the ribosome.
Topics: Animals; Cryoelectron Microscopy; Humans; Models, Molecular; Nuclear Magnetic Resonance, Biomolecular; Protein Biosynthesis; Protein Folding; Ribosomes
PubMed: 28580913
DOI: 10.1107/S2059798317007446