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Aging Cell Sep 2023Cellular senescence constitutes a generally irreversible proliferation barrier, accompanied by macromolecular damage and metabolic rewiring. Several senescence types...
Cellular senescence constitutes a generally irreversible proliferation barrier, accompanied by macromolecular damage and metabolic rewiring. Several senescence types have been identified based on the initiating stimulus, such as replicative (RS), stress-induced (SIS) and oncogene-induced senescence (OIS). These senescence subtypes are heterogeneous and often develop subset-specific phenotypes. Reduced protein synthesis is considered a senescence hallmark, but whether this trait pertains to various senescence subtypes and if distinct molecular mechanisms are involved remain largely unknown. Here, we analyze large published or experimentally produced RNA-seq and Ribo-seq datasets to determine whether major translation-regulating entities such as ribosome stalling, the presence of uORFs/dORFs and IRES elements may differentially contribute to translation deficiency in senescence subsets. We show that translation-regulating mechanisms may not be directly relevant to RS, however uORFs are significantly enriched in SIS. Interestingly, ribosome stalling, uORF/dORF patterns and IRES elements comprise predominant mechanisms upon OIS, strongly correlating with Notch pathway activation. Our study provides for the first time evidence that major translation dysregulation mechanisms/patterns occur during cellular senescence, but at different rates depending on the stimulus type. The degree at which those mechanisms accumulate directly correlates with translation deficiency levels. Our thorough analysis contributes to elucidating crucial and so far unknown differences in the translation machinery between senescence subsets.
Topics: Cellular Senescence; Ribosomes; Protein Biosynthesis
PubMed: 37547972
DOI: 10.1111/acel.13893 -
Cells Nov 2019The ribosome is a complex ribonucleoprotein-based molecular machine that orchestrates protein synthesis in the cell. Both ribosomal RNA and ribosomal proteins can be... (Review)
Review
The ribosome is a complex ribonucleoprotein-based molecular machine that orchestrates protein synthesis in the cell. Both ribosomal RNA and ribosomal proteins can be chemically modified by reactive oxygen species, which may alter the ribosome's functions or cause a complete loss of functionality. The oxidative damage that ribosomes accumulate during their lifespan in a cell may lead to reduced or faulty translation and contribute to various pathologies. However, remarkably little is known about the biological consequences of oxidative damage to the ribosome. Here, we provide a concise summary of the known types of changes induced by reactive oxygen species in rRNA and ribosomal proteins and discuss the existing experimental evidence of how these modifications may affect ribosome dynamics and function. We emphasize the special role that redox-active transition metals, such as iron, play in ribosome homeostasis and stability. We also discuss the hypothesis that redox-mediated ribosome modifications may contribute to adaptive cellular responses to stress.
Topics: Animals; Homeostasis; Humans; Iron; Oxidation-Reduction; Oxidative Stress; Protein Biosynthesis; RNA, Ribosomal; Reactive Oxygen Species; Ribosomes
PubMed: 31684095
DOI: 10.3390/cells8111379 -
RNA Biology Jan 2022The ribosome has long been thought to be a homogeneous cellular machine that constitutively and globally synthesises proteins from mRNA. However, recent studies have... (Review)
Review
The ribosome has long been thought to be a homogeneous cellular machine that constitutively and globally synthesises proteins from mRNA. However, recent studies have revealed that ribosomes are highly heterogeneous, dynamic macromolecular complexes with specialised roles in translational regulation in many organisms across the kingdoms. In this review, we summarise the current understanding of ribosome heterogeneity and the specialised functions of heterogeneous ribosomes. We also discuss specialised translation systems that utilise orthogonal ribosomes.
Topics: Protein Biosynthesis; Ribosomal Proteins; Ribosomes; RNA, Messenger; Protein Processing, Post-Translational
PubMed: 36255182
DOI: 10.1080/15476286.2022.2135299 -
Nature Feb 2023Mitochondrial ribosomes (mitoribosomes) synthesize proteins encoded within the mitochondrial genome that are assembled into oxidative phosphorylation complexes. Thus,...
Mitochondrial ribosomes (mitoribosomes) synthesize proteins encoded within the mitochondrial genome that are assembled into oxidative phosphorylation complexes. Thus, mitoribosome biogenesis is essential for ATP production and cellular metabolism. Here we used cryo-electron microscopy to determine nine structures of native yeast and human mitoribosomal small subunit assembly intermediates, illuminating the mechanistic basis for how GTPases are used to control early steps of decoding centre formation, how initial rRNA folding and processing events are mediated, and how mitoribosomal proteins have active roles during assembly. Furthermore, this series of intermediates from two species with divergent mitoribosomal architecture uncovers both conserved principles and species-specific adaptations that govern the maturation of mitoribosomal small subunits in eukaryotes. By revealing the dynamic interplay between assembly factors, mitoribosomal proteins and rRNA that are required to generate functional subunits, our structural analysis provides a vignette for how molecular complexity and diversity can evolve in large ribonucleoprotein assemblies.
Topics: Humans; Cryoelectron Microscopy; Mitochondrial Proteins; Mitochondrial Ribosomes; Ribosomal Proteins; Saccharomyces cerevisiae; RNA, Ribosomal; GTP Phosphohydrolases; Ribonucleoproteins; Fungal Proteins; Ribosome Subunits, Small
PubMed: 36482135
DOI: 10.1038/s41586-022-05621-0 -
Cells Mar 2020Mechanical forces acting on biological systems, at both the macroscopic and microscopic levels, play an important part in shaping cellular phenotypes. There is a growing... (Review)
Review
Mechanical forces acting on biological systems, at both the macroscopic and microscopic levels, play an important part in shaping cellular phenotypes. There is a growing realization that biomolecules that respond to force directly applied to them, or via mechano-sensitive signalling pathways, can produce profound changes to not only transcriptional pathways, but also in protein translation. Forces naturally occurring at the molecular level can impact the rate at which the bacterial ribosome translates messenger RNA (mRNA) transcripts and influence processes such as co-translational folding of a nascent protein as it exits the ribosome. In eukaryotes, force can also be transduced at the cellular level by the cytoskeleton, the cell's internal filamentous network. The cytoskeleton closely associates with components of the translational machinery such as ribosomes and elongation factors and, as such, is a crucial determinant of localized protein translation. In this review we will give (1) a brief overview of protein translation in bacteria and eukaryotes and then discuss (2) how mechanical forces are directly involved with ribosomes during active protein synthesis and (3) how eukaryotic ribosomes and other protein translation machinery intimately associates with the mechanosensitive cytoskeleton network.
Topics: Eukaryotic Cells; Humans; Phenotype; Protein Biosynthesis; Proteins; RNA, Messenger; Ribosomes
PubMed: 32156009
DOI: 10.3390/cells9030650 -
PloS One 2022Developing mathematical representations of biological systems that can allow predictions is a challenging and important research goal. It is demonstrated here how the...
Developing mathematical representations of biological systems that can allow predictions is a challenging and important research goal. It is demonstrated here how the ribosome, the nano-machine responsible for synthesizing all proteins necessary for cellular life, can be represented as a bipartite network. Ten ribosomal structures from Bacteria and six from Eukarya are explored. Ribosomal networks are found to exhibit unique properties despite variations in the nodes and edges of the different graphs. The ribosome is shown to exhibit very large topological redundancies, demonstrating mathematical resiliency. These results can potentially explain how it can function consistently despite changes in composition and connectivity. Furthermore, this representation can be used to analyze ribosome function within the large machinery of network theory, where the degrees of freedom are the possible interactions, and can be used to provide new insights for translation regulation and therapeutics.
Topics: Ribosomes; Proteins; Bacteria; Eukaryota
PubMed: 36584020
DOI: 10.1371/journal.pone.0279455 -
Trends in Cell Biology Sep 2022Translation factors have traditionally been viewed as proteins that drive ribosome function and ensure accurate mRNA translation. Recent discoveries have highlighted... (Review)
Review
Translation factors have traditionally been viewed as proteins that drive ribosome function and ensure accurate mRNA translation. Recent discoveries have highlighted that these factors can also moonlight in gene regulation, but through functions distinct from their canonical roles in protein synthesis. Notably, the additional functions that translation factors encode are diverse, ranging from transcriptional control and extracellular signaling to RNA binding, and are highly regulated in response to external cues and the intrinsic cellular state. Thus, this multifunctionality of translation factors provides an additional mechanism for exquisite control of gene expression.
Topics: Gene Expression Regulation; Humans; Protein Biosynthesis; Proteins; Ribosomes
PubMed: 35466028
DOI: 10.1016/j.tcb.2022.03.006 -
Cells Sep 2021The ribosome, which is present in all three domains of life, plays a well-established, critical role in the translation process by decoding messenger RNA into protein.... (Review)
Review
The ribosome, which is present in all three domains of life, plays a well-established, critical role in the translation process by decoding messenger RNA into protein. Ribosomal proteins, in contrast, appear to play non-translational roles in growth, differentiation, and disease. We recently discovered that ribosomes are involved in reverting cellular potency to a multipotent state. Ribosomal incorporation (the uptake of free ribosome by living cells) can direct the fate of both somatic and cancer cells into multipotency, allowing them to switch cell lineage. During this process, both types of cells experienced cell-cycle arrest and cellular stress while remaining multipotent. This review provides a molecular perspective on current insights into ribosome-induced multipotency and sheds light on how a common stress-associated mechanism may be involved. We also discuss the impact of this phenomenon on cancer cell reprogramming and its potential in cancer therapy.
Topics: Animals; Cell Differentiation; Cell Lineage; Germ Layers; Humans; Neoplasms; Protein Biosynthesis; RNA, Messenger; Ribosomal Proteins; Ribosomes
PubMed: 34571922
DOI: 10.3390/cells10092276 -
Nature Communications Oct 2022The ribosome is a macromolecular machine that catalyzes the sequence-defined polymerization of L-α-amino acids into polypeptides. The catalysis of peptide bond...
The ribosome is a macromolecular machine that catalyzes the sequence-defined polymerization of L-α-amino acids into polypeptides. The catalysis of peptide bond formation between amino acid substrates is based on entropy trapping, wherein the adjacency of transfer RNA (tRNA)-coupled acyl bonds in the P-site and the α-amino groups in the A-site aligns the substrates for coupling. The plasticity of this catalytic mechanism has been observed in both remnants of the evolution of the genetic code and modern efforts to reprogram the genetic code (e.g., ribosomal incorporation of non-canonical amino acids, ribosomal ester formation). However, the limits of ribosome-mediated polymerization are underexplored. Here, rather than peptide bonds, we demonstrate ribosome-mediated polymerization of pyridazinone bonds via a cyclocondensation reaction between activated γ-keto and α-hydrazino ester monomers. In addition, we demonstrate the ribosome-catalyzed synthesis of peptide-hybrid oligomers composed of multiple sequence-defined alternating pyridazinone linkages. Our results highlight the plasticity of the ribosome's ancient bond-formation mechanism, expand the range of non-canonical polymeric backbones that can be synthesized by the ribosome, and open the door to new applications in synthetic biology.
Topics: Ribosomes; RNA, Transfer; Genetic Code; Peptides; Amino Acids; Protein Biosynthesis
PubMed: 36280685
DOI: 10.1038/s41467-022-33701-2 -
International Journal of Biological... 2022Protein homeostasis is well accepted as the prerequisite for proper operation of various life activities. As the main apparatus of protein translation, ribosomes play an... (Review)
Review
Protein homeostasis is well accepted as the prerequisite for proper operation of various life activities. As the main apparatus of protein translation, ribosomes play an indispensable role in the maintenance of protein homeostasis. Nevertheless, upon stimulation of various internal and external factors, malfunction of ribosomes may be evident with the excessive production of aberrant proteins, accumulation of which can result in deleterious effects on cellular fate and even cell death. Ribosomopathies are characterized as a series of diseases caused by abnormalities of ribosomal compositions and functions. Correspondingly, cell evolves several ribosome quality control mechanisms in maintaining the quantity and quality of intracellular ribosomes, namely ribosome quality control system (RQCS). Of note, RQCS can tightly monitor the entire process from ribosome biogenesis to its degradation, with the capacity of coping with ribosomal dysfunction, including misassembled ribosomes and incorrectly synthesized ribosomal proteins. In the current literature review, we mainly introduce the RQCS and elaborate on the underlying pathogenesis of several ribosomopathies. With the in-depth understanding of ribosomal dysfunction and molecular basis of RQCS, therapeutic strategy by specifically targeting RQCS remains a promising option in treating patients with ribosomopathies and other ribosome-associated human diseases.
Topics: Eukaryota; Humans; Protein Biosynthesis; Ribosomal Proteins; Ribosomes
PubMed: 35414791
DOI: 10.7150/ijbs.70955