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Annual Review of Nutrition Sep 2020The emergence of genome-wide analyses to interrogate cellular DNA, RNA, and protein content has revolutionized the study of control networks that mediate cellular... (Review)
Review
The emergence of genome-wide analyses to interrogate cellular DNA, RNA, and protein content has revolutionized the study of control networks that mediate cellular homeostasis. mRNA translation represents the last step of genetic flow and primarily defines the proteome. Translational regulation is thus critical for gene expression, in particular under nutrient excess or deficiency. Until recently, it was unclear how the global effects of translational control are orchestrated by nutrient signaling pathways. An emerging concept of translational reprogramming addresses how to maintain the expression of specific proteins during nutrient stress by translation of selective mRNAs. In this review, we describe recent advances in our understanding of translational control principles; nutrient-sensing mechanisms; and their dysregulation in human diseases such as diabetes, cancer, and aging. The mechanistic understanding of translational regulation in response to different nutrient conditions may help identify potential dietary and therapeutic targets to improve human health.
Topics: Gene Expression Regulation; Genome-Wide Association Study; Humans; Nutrients; Protein Biosynthesis; RNA, Messenger
PubMed: 32631146
DOI: 10.1146/annurev-nutr-120919-041411 -
Cell Systems Jun 2021Molecular translation systems provide a genetically encoded framework for protein synthesis, which is essential for all life. Engineering these systems to incorporate... (Review)
Review
Molecular translation systems provide a genetically encoded framework for protein synthesis, which is essential for all life. Engineering these systems to incorporate non-canonical amino acids (ncAAs) into peptides and proteins has opened many exciting opportunities in chemical and synthetic biology. Here, we review recent advances that are transforming our ability to engineer molecular translation systems. In cell-based systems, new processes to synthesize recoded genomes, tether ribosomal subunits, and engineer orthogonality with high-throughput workflows have emerged. In cell-free systems, adoption of flexizyme technology and cell-free ribosome synthesis and evolution platforms are expanding the limits of chemistry at the ribosome's RNA-based active site. Looking forward, innovations will deepen understanding of molecular translation and provide a path to polymers with previously unimaginable structures and functions.
Topics: Amino Acids; Cell-Free System; Protein Biosynthesis; Proteins; Synthetic Biology
PubMed: 34139167
DOI: 10.1016/j.cels.2021.04.001 -
Wiley Interdisciplinary Reviews. RNA Jul 2021Protein metabolism plays central roles in age-related decline and neurodegeneration. While a large body of research has explored age-related changes in protein... (Review)
Review
Protein metabolism plays central roles in age-related decline and neurodegeneration. While a large body of research has explored age-related changes in protein degradation, alterations in the efficiency and fidelity of protein synthesis with aging are less well understood. Age-associated changes occur in both the protein synthetic machinery (ribosomal proteins and rRNA) and within regulatory factors controlling translation. At the same time, many of the interventions that prolong lifespan do so in part by pre-emptively decreasing protein synthesis rates to allow better harmonization to age-related declines in protein catabolism. Here we review the roles of translation regulation in aging, with a specific focus on factors implicated in age-related neurodegeneration. We discuss how emerging technologies such as ribosome profiling and superior mass spectrometric approaches are illuminating age-dependent mRNA-specific changes in translation rates across tissues to reveal a critical interplay between catabolic and anabolic pathways that likely contribute to functional decline. These new findings point to nodes in posttranscriptional gene regulation that both contribute to aging and offer targets for therapy. This article is categorized under: Translation > Translation Regulation Translation > Ribosome Biogenesis Translation > Translation Mechanisms.
Topics: Aging; Humans; Neurodegenerative Diseases; Protein Biosynthesis; RNA, Messenger; RNA, Ribosomal; Ribosomal Proteins; Ribosomes
PubMed: 32954679
DOI: 10.1002/wrna.1628 -
Nature Reviews. Genetics Mar 2021The encoded biosynthesis of proteins provides the ultimate paradigm for high-fidelity synthesis of long polymers of defined sequence and composition, but it is limited... (Review)
Review
The encoded biosynthesis of proteins provides the ultimate paradigm for high-fidelity synthesis of long polymers of defined sequence and composition, but it is limited to polymerizing the canonical amino acids. Recent advances have built on genetic code expansion - which commonly permits the cellular incorporation of one type of non-canonical amino acid into a protein - to enable the encoded incorporation of several distinct non-canonical amino acids. Developments include strategies to read quadruplet codons, use non-natural DNA base pairs, synthesize completely recoded genomes and create orthogonal translational components with reprogrammed specificities. These advances may enable the genetically encoded synthesis of non-canonical biopolymers and provide a platform for transforming the discovery and evolution of new materials and therapeutics.
Topics: Amino Acids; Animals; Cellular Reprogramming; Codon; DNA; Genetic Code; Humans; Protein Biosynthesis; Proteins
PubMed: 33318706
DOI: 10.1038/s41576-020-00307-7 -
Molecular Cell Feb 2023Viral reproduction is contingent on viral protein synthesis that relies on the host ribosomes. As such, viruses have evolved remarkable strategies to hijack the host... (Review)
Review
Viral reproduction is contingent on viral protein synthesis that relies on the host ribosomes. As such, viruses have evolved remarkable strategies to hijack the host translational apparatus in order to favor viral protein production and to interfere with cellular innate defenses. Here, we describe the approaches viruses use to exploit the translation machinery, focusing on commonalities across diverse viral families, and discuss the functional relevance of this process. We illustrate the complementary strategies host cells utilize to block viral protein production and consider how cells ensure an efficient antiviral response that relies on translation during this tug of war over the ribosome. Finally, we highlight potential roles mRNA modifications and ribosome quality control play in translational regulation and innate immunity. We address these topics in the context of the COVID-19 pandemic and focus on the gaps in our current knowledge of these mechanisms, specifically in viruses with pandemic potential.
Topics: Humans; COVID-19; Pandemics; Protein Biosynthesis; RNA, Viral; Viral Proteins; Virus Diseases; Viruses; Ribosomes
PubMed: 36334591
DOI: 10.1016/j.molcel.2022.10.012 -
Nucleic Acids Research Feb 2020During canonical translation, the ribosome moves along an mRNA from the start to the stop codon in exact steps of one codon at a time. The collinearity of the mRNA and... (Review)
Review
During canonical translation, the ribosome moves along an mRNA from the start to the stop codon in exact steps of one codon at a time. The collinearity of the mRNA and the protein sequence is essential for the quality of the cellular proteome. Spontaneous errors in decoding or translocation are rare and result in a deficient protein. However, dedicated recoding signals in the mRNA can reprogram the ribosome to read the message in alternative ways. This review summarizes the recent advances in understanding the mechanisms of three types of recoding events: stop-codon readthrough, -1 ribosome frameshifting and translational bypassing. Recoding events provide insights into alternative modes of ribosome dynamics that are potentially applicable to other non-canonical modes of prokaryotic and eukaryotic translation.
Topics: Codon, Terminator; Frameshifting, Ribosomal; Protein Biosynthesis; Ribosomes
PubMed: 31511883
DOI: 10.1093/nar/gkz783 -
The Journal of Biological Chemistry Nov 2019Protein chains contain only l-amino acids, with the exception of the achiral glycine, making the chains homochiral. This homochirality is a prerequisite for proper... (Review)
Review
Protein chains contain only l-amino acids, with the exception of the achiral glycine, making the chains homochiral. This homochirality is a prerequisite for proper protein folding and, hence, normal cellular function. The importance of d-amino acids as a component of the bacterial cell wall and their roles in neurotransmission in higher eukaryotes are well-established. However, the wider presence and the corresponding physiological roles of these specific amino acid stereoisomers have been appreciated only recently. Therefore, it is expected that enantiomeric fidelity has to be a key component of all of the steps in translation. Cells employ various molecular mechanisms for keeping d-amino acids away from the synthesis of nascent polypeptide chains. The major factors involved in this exclusion are aminoacyl-tRNA synthetases (aaRSs), elongation factor thermo-unstable (EF-Tu), the ribosome, and d-aminoacyl-tRNA deacylase (DTD). aaRS, EF-Tu, and the ribosome act as "chiral checkpoints" by preferentially binding to l-amino acids or l-aminoacyl-tRNAs, thereby excluding d-amino acids. Interestingly, DTD, which is conserved across all life forms, performs "chiral proofreading," as it removes d-amino acids erroneously added to tRNA. Here, we comprehensively review d-amino acids with respect to their occurrence and physiological roles, implications for chiral checkpoints required for translation fidelity, and potential use in synthetic biology.
Topics: Amino Acids; Amino Acyl-tRNA Synthetases; Bacteria; Bacterial Proteins; Cell Wall; Peptide Elongation Factor Tu; Protein Biosynthesis; Ribosomes; Stereoisomerism
PubMed: 31591268
DOI: 10.1074/jbc.REV119.008166 -
Molecular Cell Apr 2021Eukaryotic cells integrate multiple quality control (QC) responses during protein synthesis in the cytoplasm. These QC responses are signaled by slow or stalled... (Review)
Review
Eukaryotic cells integrate multiple quality control (QC) responses during protein synthesis in the cytoplasm. These QC responses are signaled by slow or stalled elongating ribosomes. Depending on the nature of the delay, the signal may lead to translational repression, messenger RNA decay, ribosome rescue, and/or nascent protein degradation. Here, we discuss how the structure and composition of an elongating ribosome in a troubled state determine the downstream quality control pathway(s) that ensue. We highlight the intersecting pathways involved in RNA decay and the crosstalk that occurs between RNA decay and ribosome rescue.
Topics: Animals; Eukaryotic Cells; Humans; Protein Biosynthesis; RNA Stability; RNA, Messenger; Ribosomes
PubMed: 33713598
DOI: 10.1016/j.molcel.2021.02.022 -
Trends in Biochemical Sciences Sep 2021Ribosomes that stall inappropriately during protein synthesis harbor proteotoxic components linked to cellular stress and neurodegenerative diseases. Molecular... (Review)
Review
Ribosomes that stall inappropriately during protein synthesis harbor proteotoxic components linked to cellular stress and neurodegenerative diseases. Molecular mechanisms that rescue stalled ribosomes must selectively detect rare aberrant translational complexes and process the heterogeneous components. Ribosome-associated quality control pathways eliminate problematic messenger RNAs and nascent proteins on stalled translational complexes. In addition, recent studies have uncovered general principles of stall recognition upstream of quality control pathways and fail-safe mechanisms that ensure nascent proteome integrity. Here, we discuss developments in our mechanistic understanding of the detection and rescue of stalled ribosomal complexes in eukaryotes.
Topics: Protein Biosynthesis; Protein Processing, Post-Translational; Proteins; RNA, Messenger; Ribosomes
PubMed: 33966939
DOI: 10.1016/j.tibs.2021.03.008 -
Genomics Jan 2021Deregulation of protein synthesis may be involved in multiple aspects of cancer, such as gene expression, signal transduction and drive specific cell biological... (Review)
Review
Deregulation of protein synthesis may be involved in multiple aspects of cancer, such as gene expression, signal transduction and drive specific cell biological responses, resulting in promoting cancer growth, invasion and metastasis. Study the molecular mechanisms about translational control may help us to find more effective anti-cancer drugs and develop novel therapeutic opportunities. Recently, the researchers had focused on targeting translational machinery to overcome cancer, and various small molecular inhibitors targeting translation factors or pathways have been tested in clinical trials and exhibited improving outcomes in several cancer types. There is no doubt that an insight into the class of translation regulation protein would provide new target for pharmacologic intervention and further provide opportunities to develop novel anti-tumor therapeutic interventions. In this review, we summarized the developments of translational control in cancer survival and progression et al, and highlighted the therapeutic approach targeted translation regulation to overcome the cancer.
Topics: Animals; Antineoplastic Agents; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Protein Biosynthesis; Ribosomal Proteins
PubMed: 33189778
DOI: 10.1016/j.ygeno.2020.11.011