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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 -
Biochemistry. Biokhimiia Aug 2021During protein synthesis, ribosome moves along mRNA to decode one codon after the other. Ribosome translocation is induced by a universally conserved protein, elongation... (Review)
Review
During protein synthesis, ribosome moves along mRNA to decode one codon after the other. Ribosome translocation is induced by a universally conserved protein, elongation factor G (EF-G) in bacteria and elongation factor 2 (EF-2) in eukaryotes. EF-G-induced translocation results in unwinding of the intramolecular secondary structures of mRNA by three base pairs at a time that renders the translating ribosome a processive helicase. Professor Alexander Sergeevich Spirin has made numerous seminal contributions to understanding the molecular mechanism of translocation. Here, we review Spirin's insights into the ribosomal translocation and recent advances in the field that stemmed from Spirin's pioneering work. We also discuss key remaining challenges in studies of translocase and helicase activities of the ribosome.
Topics: Biological Transport; Cryoelectron Microscopy; Eukaryota; Fluorescence Resonance Energy Transfer; Models, Molecular; Peptide Elongation Factor 2; Peptide Elongation Factor G; Protein Biosynthesis; RNA Helicases; RNA, Messenger; RNA, Transfer; Ribosomes; Transferases
PubMed: 34488575
DOI: 10.1134/S0006297921080095 -
Cell Death & Disease Jul 2023Impairment of protein translation can cause stalling and collision of ribosomes and is a signal for the activation of ribosomal surveillance and rescue pathways. Despite...
Impairment of protein translation can cause stalling and collision of ribosomes and is a signal for the activation of ribosomal surveillance and rescue pathways. Despite clear evidence that ribosome collision occurs stochastically at a cellular and organismal level, physiologically relevant sources of such aberrations are poorly understood. Here we show that a burst of the cellular signaling molecule nitric oxide (NO) reduces translational activity and causes ribosome collision in human cell lines. This is accompanied by activation of the ribotoxic stress response, resulting in ZAKα-mediated activation of p38 and JNK kinases. In addition, NO production is associated with ZNF598-mediated ubiquitination of the ribosomal protein RPS10 and GCN2-mediated activation of the integrated stress response, which are well-described responses to the collision of ribosomes. In sum, our work implicates a novel role of NO as an inducer of ribosome collision and activation of ribosomal surveillance mechanisms in human cells.
Topics: Humans; Nitric Oxide; Ribosomes; Protein Biosynthesis; Ribosomal Proteins; Ubiquitination; Carrier Proteins
PubMed: 37495584
DOI: 10.1038/s41419-023-05997-5 -
Wiley Interdisciplinary Reviews. RNA Jul 2021Regulation of protein synthesis is a vital step in controlling gene expression, especially during development. Over the last 10 years, it has become clear that rather... (Review)
Review
Regulation of protein synthesis is a vital step in controlling gene expression, especially during development. Over the last 10 years, it has become clear that rather than being homogeneous machines responsible for mRNA translation, ribosomes are highly heterogeneous and can play an active part in translational regulation. These "specialized ribosomes" comprise of specific protein and/or rRNA components, which are required for the translation of particular mRNAs. However, while there is extensive evidence for ribosome heterogeneity, support for specialized functions is limited. Recent work in a variety of developmental model organisms has shed some light on the biological relevance of ribosome heterogeneity. Tissue-specific expression of ribosomal components along with phenotypic analysis of ribosomal gene mutations indicate that ribosome heterogeneity and potentially specialization are common in key development processes like embryogenesis, spermatogenesis, oogenesis, body patterning, and neurogenesis. Several examples of ribosome specialization have now been proposed but strong links between ribosome heterogeneity, translation of specific mRNAs by defined mechanisms, and role of these translation events remain elusive. Furthermore, several studies have indicated that heterogeneous ribosome populations are a product of tissue-specific expression rather than specialized function and that ribosomal protein phenotypes are the result of extra-ribosomal function or overall reduced ribosome levels. Many important questions still need to be addressed in order to determine the functional importance of ribosome heterogeneity to development and disease, which is likely to vary across systems. It will be essential to dissect these issues to fully understand diseases caused by disruptions to ribosomal composition, such as ribosomopathies. This article is categorized under: Translation > Translation Regulation Translation > Ribosome Structure/Function RNA in Disease and Development > RNA in Development.
Topics: Gene Expression Regulation, Developmental; Protein Biosynthesis; RNA, Messenger; RNA, Ribosomal; Ribosomal Proteins; Ribosomes
PubMed: 33565275
DOI: 10.1002/wrna.1644 -
RNA Biology Jan 2022Eukaryotic ribosome biogenesis involves the synthesis of ribosomal RNA (rRNA) and its stepwise folding into the unique structure present in mature ribosomes. rRNA... (Review)
Review
Eukaryotic ribosome biogenesis involves the synthesis of ribosomal RNA (rRNA) and its stepwise folding into the unique structure present in mature ribosomes. rRNA folding starts already co-transcriptionally in the nucleolus and continues when pre-ribosomal particles further maturate in the nucleolus and upon their transit to the nucleoplasm and cytoplasm. While the approximate order of folding of rRNA subdomains is known, especially from cryo-EM structures of pre-ribosomal particles, the actual mechanisms of rRNA folding are less well understood. Both small nucleolar RNAs (snoRNAs) and proteins have been implicated in rRNA folding. snoRNAs hybridize to precursor rRNAs (pre-rRNAs) and thereby prevent premature folding of the respective rRNA elements. Ribosomal proteins (r-proteins) and ribosome assembly factors might have a similar function by binding to rRNA elements and preventing their premature folding. Besides that, a small group of ribosome assembly factors are thought to play a more active role in rRNA folding. In particular, multiple RNA helicases participate in individual ribosome assembly steps, where they are believed to coordinate RNA folding/unfolding events or the release of proteins from the rRNA. In this review, we summarize the current knowledge on mechanisms of RNA folding and on the specific function of the individual RNA helicases involved. As the yeast is the organism in which ribosome biogenesis and the role of RNA helicases in this process is best studied, we focused our review on insights from this model organism, but also make comparisons to other organisms where applicable.
Topics: RNA Folding; RNA Helicases; RNA Precursors; RNA, Ribosomal; RNA, Small Nucleolar; Ribosomal Proteins; Ribosomes; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 35678541
DOI: 10.1080/15476286.2022.2079890 -
International Journal of Molecular... Apr 2023Ribosomes, in general, are viewed as constitutive macromolecular machines where protein synthesis takes place; however, this view has been recently challenged,... (Review)
Review
Ribosomes, in general, are viewed as constitutive macromolecular machines where protein synthesis takes place; however, this view has been recently challenged, supporting the hypothesis of ribosome specialization and opening a completely new field of research. Recent studies have demonstrated that ribosomes are heterogenous in their nature and can provide another layer of gene expression control by regulating translation. Heterogeneities in ribosomal RNA and ribosomal proteins that compose them favor the selective translation of different sub-pools of mRNAs and functional specialization. In recent years, the heterogeneity and specialization of ribosomes have been widely reported in different eukaryotic study models; however, few reports on this topic have been made on protozoa and even less on protozoa parasites of medical importance. This review analyzes heterogeneities of ribosomes in protozoa parasites highlighting the specialization in their functions and their importance in parasitism, in the transition between stages in their life cycle, in the change of host and in response to environmental conditions.
Topics: Animals; Parasites; Protein Biosynthesis; Ribosomes; Ribosomal Proteins; RNA, Ribosomal
PubMed: 37108644
DOI: 10.3390/ijms24087484 -
Annual Review of Biophysics May 2023Faithful translation of messenger RNA (mRNA) into protein is essential to maintain protein homeostasis in the cell. Spontaneous translation errors are very rare due to... (Review)
Review
Faithful translation of messenger RNA (mRNA) into protein is essential to maintain protein homeostasis in the cell. Spontaneous translation errors are very rare due to stringent selection of cognate aminoacyl transfer RNAs (tRNAs) and the tight control of the mRNA reading frame by the ribosome. Recoding events, such as stop codon readthrough, frameshifting, and translational bypassing, reprogram the ribosome to make intentional mistakes and produce alternative proteins from the same mRNA. The hallmark of recoding is the change of ribosome dynamics. The signals for recoding are built into the mRNA, but their reading depends on the genetic makeup of the cell, resulting in cell-specific changes in expression programs. In this review, I discuss the mechanisms of canonical decoding and tRNA-mRNA translocation; describe alternative pathways leading to recoding; and identify the links among mRNA signals, ribosome dynamics, and recoding.
Topics: Proteostasis; RNA, Messenger; Ribosomes
PubMed: 37159300
DOI: 10.1146/annurev-biophys-101922-072452 -
Development (Cambridge, England) Mar 2023Although differential transcription drives the development of multicellular organisms, the ultimate readout of a protein-coding gene is ribosome-dependent mRNA... (Review)
Review
Although differential transcription drives the development of multicellular organisms, the ultimate readout of a protein-coding gene is ribosome-dependent mRNA translation. Ribosomes were once thought of as uniform molecular machines, but emerging evidence indicates that the complexity and diversity of ribosome biogenesis and function should be given a fresh look in the context of development. This Review begins with a discussion of different developmental disorders that have been linked with perturbations in ribosome production and function. We then highlight recent studies that reveal how different cells and tissues exhibit variable levels of ribosome production and protein synthesis, and how changes in protein synthesis capacity can influence specific cell fate decisions. We finish by touching upon ribosome heterogeneity in stress responses and development. These discussions highlight the importance of considering both ribosome levels and functional specialization in the context of development and disease.
Topics: Ribosomes; Protein Biosynthesis; Cell Differentiation; Ribosomal Proteins
PubMed: 36897354
DOI: 10.1242/dev.201187 -
Cells Oct 2020Many studies have focused on understanding the regulation and functions of aberrant protein synthesis in colorectal cancer (CRC), leaving the ribosome, its main... (Review)
Review
Many studies have focused on understanding the regulation and functions of aberrant protein synthesis in colorectal cancer (CRC), leaving the ribosome, its main effector, relatively underappreciated in CRC. The production of functional ribosomes is initiated in the nucleolus, requires coordinated ribosomal RNA (rRNA) processing and ribosomal protein (RP) assembly, and is frequently hyperactivated to support the needs in protein synthesis essential to withstand unremitting cancer cell growth. This elevated ribosome production in cancer cells includes a strong alteration of ribosome biogenesis homeostasis that represents one of the hallmarks of cancer cells. None of the ribosome production steps escape this cancer-specific dysregulation. This review summarizes the early and late steps of ribosome biogenesis dysregulations described in CRC cell lines, intestinal organoids, CRC stem cells and mouse models, and their possible clinical implications. We highlight how this cancer-related ribosome biogenesis, both at quantitative and qualitative levels, can lead to the synthesis of ribosomes favoring the translation of mRNAs encoding hyperproliferative and survival factors. We also discuss whether cancer-related ribosome biogenesis is a mere consequence of cancer progression or is a causal factor in CRC, and how altered ribosome biogenesis pathways can represent effective targets to kill CRC cells. The association between exacerbated CRC cell growth and alteration of specific steps of ribosome biogenesis is highlighted as a key driver of tumorigenesis, providing promising perspectives for the implementation of predictive biomarkers and the development of new therapeutic drugs.
Topics: Animals; Colorectal Neoplasms; Genes, Tumor Suppressor; Humans; Models, Biological; Organelle Biogenesis; RNA, Ribosomal; Ribosomes
PubMed: 33120992
DOI: 10.3390/cells9112361 -
Cell Reports Mar 2024Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hinders host gene expression, curbing defenses and licensing viral protein synthesis and virulence. During...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hinders host gene expression, curbing defenses and licensing viral protein synthesis and virulence. During SARS-CoV-2 infection, the virulence factor non-structural protein 1 (Nsp1) targets the mRNA entry channel of mature cytoplasmic ribosomes, limiting translation. We show that Nsp1 also restrains translation by targeting nucleolar ribosome biogenesis. SARS-CoV-2 infection disrupts 18S and 28S ribosomal RNA (rRNA) processing. Expression of Nsp1 recapitulates the processing defects. Nsp1 abrogates rRNA production without altering the expression of critical processing factors or nucleolar organization. Instead, Nsp1 localizes to the nucleolus, interacting with precursor-rRNA and hindering its maturation separately from the viral protein's role in restricting mature ribosomes. Thus, SARS-CoV-2 Nsp1 limits translation by targeting ribosome biogenesis and mature ribosomes. These findings revise our understanding of how SARS-CoV-2 Nsp1 controls human protein synthesis, suggesting that efforts to counter Nsp1's effect on translation should consider the protein's impact from ribosome manufacturing to mature ribosomes.
Topics: Humans; SARS-CoV-2; RNA, Ribosomal; COVID-19; Ribosomes; Viral Proteins; Viral Nonstructural Proteins
PubMed: 38427561
DOI: 10.1016/j.celrep.2024.113891