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Biomolecules Jan 2020Many proteins in the cell fold cotranslationally within the restricted space of the polypeptide exit tunnel or at the surface of the ribosome. A growing body of evidence... (Review)
Review
Many proteins in the cell fold cotranslationally within the restricted space of the polypeptide exit tunnel or at the surface of the ribosome. A growing body of evidence suggests that the ribosome can alter the folding trajectory in many different ways. In this review, we summarize the recent examples of how translation affects folding of single-domain, multiple-domain and oligomeric proteins. The vectorial nature of translation, the spatial constraints of the exit tunnel, and the electrostatic properties of the ribosome-nascent peptide complex define the onset of early folding events. The ribosome can facilitate protein compaction, induce the formation of intermediates that are not observed in solution, or delay the onset of folding. Examples of single-domain proteins suggest that early compaction events can define the folding pathway for some types of domain structures. Folding of multi-domain proteins proceeds in a domain-wise fashion, with each domain having its role in stabilizing or destabilizing neighboring domains. Finally, the assembly of protein complexes can also begin cotranslationally. In all these cases, the ribosome helps the nascent protein to attain a native fold and avoid the kinetic traps of misfolding.
Topics: Animals; Humans; Kinetics; Models, Molecular; Protein Biosynthesis; Protein Domains; Protein Folding; Protein Modification, Translational; Proteins; Ribosomes
PubMed: 31936054
DOI: 10.3390/biom10010097 -
Nucleic Acids Research Feb 2020
Topics: Protein Biosynthesis; Ribosomes
PubMed: 32067046
DOI: 10.1093/nar/gkz1217 -
Trends in Cancer Jan 2021Ribosome biogenesis (RiBi) is one of the most complex and energy demanding processes in human cells, critical for cell growth and proliferation. Strong causal links... (Review)
Review
Ribosome biogenesis (RiBi) is one of the most complex and energy demanding processes in human cells, critical for cell growth and proliferation. Strong causal links between inherited and acquired impairment in RiBi with cancer pathogenesis are emerging, pointing to RiBi as an attractive therapeutic target for cancer. Here, we will highlight new knowledge about causes of excessive or impaired RiBi and the impact of these changes on protein synthesis. We will also discuss how new knowledge about secondary consequences of dysregulated RiBi and protein synthesis, including proteotoxic stress, metabolic alterations, adaptive transcriptional and translational programs, and the impaired ribosome biogenesis checkpoint (IRBC) provide a foundation for the development of new anticancer therapies.
Topics: Benzothiazoles; Carcinogenesis; DNA Repair; Humans; Mutation; Naphthyridines; Neoplasms; Organelle Biogenesis; Protein Biosynthesis; Proteolysis; Proto-Oncogene Proteins c-mdm2; RNA Polymerase I; Ribosomal Proteins; Ribosomes; Signal Transduction; Synthetic Lethal Mutations; Tumor Suppressor Protein p53; Ubiquitination
PubMed: 32948502
DOI: 10.1016/j.trecan.2020.08.003 -
Progress in Molecular Biology and... 2021Translational control plays a fundamental role in the regulation of gene expression in eukaryotes. Modulating translational efficiency allows the cell to fine-tune the...
Translational control plays a fundamental role in the regulation of gene expression in eukaryotes. Modulating translational efficiency allows the cell to fine-tune the expression of genes, spatially control protein localization, and trigger fast responses to environmental stresses. Translational regulation involves mechanisms acting on multiple steps of the protein synthesis pathway: initiation, elongation, and termination. Many cis-acting elements present in the 5' UTR of transcripts can influence translation at the initiation step. Among them, the Kozak sequence impacts translational efficiency by regulating the recognition of the start codon; upstream open reading frames (uORFs) are associated with inhibition of translation of the downstream protein; internal ribosomal entry sites (IRESs) can promote cap-independent translation. CRISPR-Cas technology is a revolutionary gene-editing tool that has also been applied to the regulation of gene expression. In this chapter, we focus on the genome editing approaches developed to modulate the translational efficiency with the aim to find novel therapeutic approaches, in particular acting on the cis-elements, that regulate the initiation of protein synthesis.
Topics: 5' Untranslated Regions; Gene Editing; Genetic Therapy; Open Reading Frames; Protein Biosynthesis
PubMed: 34175050
DOI: 10.1016/bs.pmbts.2021.01.028 -
Nature Reviews. Cancer Feb 2021
Topics: Humans; Neurons; Pancreatic Neoplasms; Protein Biosynthesis; Serine
PubMed: 33262455
DOI: 10.1038/s41568-020-00324-y -
Clinical & Translational Oncology :... Dec 2020Circular RNAs (circRNAs) have been considered a special class of non-coding RNAs without 5' caps and 3' tails which are covalently closed RNA molecules generated by back... (Review)
Review
Circular RNAs (circRNAs) have been considered a special class of non-coding RNAs without 5' caps and 3' tails which are covalently closed RNA molecules generated by back splicing of mRNA. For a long time, circRNAs have been considered to be directly involved in various biological processes as functional RNA. In recent years, a variety of circRNAs have been found to have translational functions, and the resultant peptides also play biological roles in the emergence and progression of human disease. The discovery of these circRNAs and their encoded peptides has enriched genomics, helped us to study the causes of diseases, and promoted the development of biotechnology. The purpose of this review is to summarize the research progress of the detection methods, translation initiation mechanism, as well as functional mechanism of peptides encoded by circRNAs, with the goal of providing the directions for the discovery of biomarkers for diagnosis, prognosis, and therapeutic targets for human disease.
Topics: Biomarkers; Diagnosis; Humans; Internal Ribosome Entry Sites; Open Reading Frames; Peptides; Prognosis; Protein Biosynthesis; RNA Caps; RNA, Circular; RNA, Messenger; Research; Therapeutics
PubMed: 32449127
DOI: 10.1007/s12094-020-02371-1 -
Amino Acids Dec 2021Proline is a non-essential amino acid with key roles in protein structure/function and maintenance of cellular redox homeostasis. It is available from dietary sources,... (Review)
Review
Proline is a non-essential amino acid with key roles in protein structure/function and maintenance of cellular redox homeostasis. It is available from dietary sources, generated de novo within cells, and released from protein structures; a noteworthy source being collagen. Its catabolism within cells can generate ATP and reactive oxygen species (ROS). Recent findings suggest that proline biosynthesis and catabolism are essential processes in disease; not only due to the role in new protein synthesis as part of pathogenic processes but also due to the impact of proline metabolism on the wider metabolic network through its significant role in redox homeostasis. This is particularly clear in cancer proliferation and metastatic outgrowth. Nevertheless, the precise identity of the drivers of cellular proline catabolism and biosynthesis, and the overall cost of maintaining appropriate balance is not currently known. In this review, we explore the major drivers of proline availability and consumption at a local and systemic level with a focus on cancer. Unraveling the main factors influencing proline metabolism in normal physiology and disease will shed light on new effective treatment strategies.
Topics: Animals; Homeostasis; Humans; Neoplasms; Oxidation-Reduction; Proline; Protein Biosynthesis; Reactive Oxygen Species
PubMed: 34291343
DOI: 10.1007/s00726-021-03051-2 -
Biochemical Society Transactions Dec 2022Protein synthesis is dysregulated in the majority of cancers and this process therefore provides a good therapeutic target. Many novel anti-cancer agents are directed to... (Review)
Review
Protein synthesis is dysregulated in the majority of cancers and this process therefore provides a good therapeutic target. Many novel anti-cancer agents are directed to target the initiation stage of translation, however, translation elongation also holds great potential as a therapeutic target. The elongation factor eIF5A that assists the formation of peptidyl bonds during the elongation process is of considerable interest in this regard. Overexpression of eIF5A has been linked with the development of a variety of cancers and inhibitors of the molecule have been proposed for anti-cancer clinical applications. eIF5A is the only protein in the cell that contains the post-translational modification hypusine. Hypusination is a two-step enzymatic process catalysed by the Deoxyhypusine Synthase (DHPS) and Deoxyhypusine Hydroxylase (DOHH). In addition, eIF5A can be acetylated by p300/CBP-associated factor (PCAF) which leads to translocation of the protein to the nucleus and its deactivation. In addition to the nucleus, eIF5A has been found in the mitochondria and the endoplasmic reticulum (ER) with eIF5A localisation related to function from regulation of mitochondrial activity and apoptosis to maintenance of ER integrity and control of the unfolded protein response (UPR). Given the pleiotropic functions of eIF5A and by extension the hypusination enzymes, this system is being considered as a target for a range of cancers including multiple myeloma, B-Cell lymphoma, and neuroblastoma. In this review, we explore the role of eIF5A and discuss the therapeutic strategies that are currently developing both in the pre- and the clinical stage.
Topics: Peptide Initiation Factors; Protein Biosynthesis; Protein Processing, Post-Translational; Apoptosis; Neoplasms
PubMed: 36511302
DOI: 10.1042/BST20221035 -
RNA Biology Jan 2023RNA modifications play a vital role in multiple pathways of mRNA metabolism, and translational regulation is essential for immune cells to promptly respond to stimuli... (Review)
Review
RNA modifications play a vital role in multiple pathways of mRNA metabolism, and translational regulation is essential for immune cells to promptly respond to stimuli and adapt to the microenvironment. N6-methyladenosine (mA) methylation, which is the most abundant mRNA modification in eukaryotes, primarily functions in the regulation of RNA splicing and degradation. However, the role of mAmethylation in translational control and its underlying mechanism remain controversial. The role of mA methylation in translation regulation in immune cells has received relatively limited attention. In this review, we aim to provide a comprehensive summary of current studies on the translational regulation of mA modifications and recent advances in understanding the translational control regulated by RNA modifications during the immune response. Furthermore, we envision the possible pathways through which mA modifications may be involved in the regulation of immune cell function via translational control.
Topics: Protein Biosynthesis; RNA; Immune System; Protein Processing, Post-Translational; RNA-Binding Proteins; Humans; Animals; Methylation
PubMed: 37584554
DOI: 10.1080/15476286.2023.2246256 -
IUBMB Life Feb 2020The endoplasmic reticulum (ER) receives unfolded proteins predestined for the secretory pathway or to be incorporated as transmembrane proteins. The ER has to... (Review)
Review
The endoplasmic reticulum (ER) receives unfolded proteins predestined for the secretory pathway or to be incorporated as transmembrane proteins. The ER has to accommodate the proper folding and glycosylation of these proteins and also to properly incorporate transmembrane proteins. However, under various circumstances, the proteins shuttling through the ER can be misfolded and undergo aggregation, which causes activation of the unfolded protein response (UPR). The UPR is mediated through three primary pathways: activating transcription factor-6, inositol-requiring enzyme-1 (IRE1), and PKR-like endoplasmic reticulum kinase, which up-regulate ER folding chaperones and temporarily suppress protein translation. The UPR can be both cytoprotective and/or cytotoxic depending on the duration of UPR activation and the type of host cell. Proteostasis controls stem cell function, while stress responses affect stem cell identity and differentiation. The present review aimed to explore and discuss the effects of the UPR pathways on mesenchymal stem cells.
Topics: Animals; Endoplasmic Reticulum; Humans; Mesenchymal Stem Cells; Protein Biosynthesis; Signal Transduction; Unfolded Protein Response
PubMed: 31444957
DOI: 10.1002/iub.2154