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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 -
Trends in Biochemical Sciences Apr 2020The collection of chemically different protein variants, or proteoforms, by far exceeds the number of protein-coding genes in the human genome. Major contributors are... (Review)
Review
The collection of chemically different protein variants, or proteoforms, by far exceeds the number of protein-coding genes in the human genome. Major contributors are alternative splicing and protein modifications. In this review, we focus on those proteoforms that differ at their N termini with a molecular link to disease. We describe the main underlying mechanisms that give rise to such N-terminal proteoforms, these being splicing, initiation of protein translation, and protein modifications. Given their role in several human diseases, it is becoming increasingly clear that several of these N-terminal proteoforms may have potential as therapeutic interventions and/or for diagnosing and prognosing their associated disease.
Topics: Alternative Splicing; Humans; Protein Biosynthesis; Protein Processing, Post-Translational
PubMed: 32001092
DOI: 10.1016/j.tibs.2019.12.009 -
Trends in Genetics : TIG Nov 2022One gene does not equal one RNA or protein. The genomic revolution has revealed numerous different RNA and protein molecules that can be produced from one gene, such as... (Review)
Review
One gene does not equal one RNA or protein. The genomic revolution has revealed numerous different RNA and protein molecules that can be produced from one gene, such as circular RNAs generated by back-splicing, proteins with residues mismatching the genomic encoding because of RNA editing, and proteins extended in the C terminus via stop codon readthrough in translation. Are these diverse products results of exquisite gene regulations or imprecise biological processes? While there are cases where the gene product diversity appears beneficial, genome-scale patterns suggest that much of this diversity arises from nonadaptive, molecular errors. This finding has important implications for studying the functions of diverse gene products and for understanding the fundamental properties and evolution of cellular life.
Topics: Codon, Terminator; Gene Expression Regulation; Genome; Protein Biosynthesis; RNA Editing; RNA, Circular
PubMed: 35641344
DOI: 10.1016/j.tig.2022.05.002 -
The Neuroscientist : a Review Journal... Feb 2020Although historically research has focused on transcription as the central governor of protein expression, protein translation is now increasingly being recognized as a... (Review)
Review
Although historically research has focused on transcription as the central governor of protein expression, protein translation is now increasingly being recognized as a major factor for determining protein levels within cells. The central nervous system relies on efficient updating of the protein landscape. Thus, coordinated regulation of mRNA localization, initiation, or termination of translation is essential for proper brain function. In particular, dendritic protein synthesis plays a key role in synaptic plasticity underlying learning and memory as well as cognitive processes. Increasing evidence suggests that impaired mRNA translation is a common feature found in numerous psychiatric disorders. In this review, we describe how malfunction of translation contributes to development of psychiatric diseases, including schizophrenia, major depression, bipolar disorder, and addiction.
Topics: Animals; Bipolar Disorder; Depressive Disorder, Major; Humans; Memory; Neuronal Plasticity; Protein Biosynthesis; Schizophrenia
PubMed: 31271100
DOI: 10.1177/1073858419853236 -
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 -
Cold Spring Harbor Perspectives in... Apr 2019The vast majority of eukaryotic messenger RNAs (mRNAs) initiate translation through a canonical, cap-dependent mechanism requiring a free 5' end and 5' cap and several... (Review)
Review
The vast majority of eukaryotic messenger RNAs (mRNAs) initiate translation through a canonical, cap-dependent mechanism requiring a free 5' end and 5' cap and several initiation factors to form a translationally active ribosome. Stresses such as hypoxia, apoptosis, starvation, and viral infection down-regulate cap-dependent translation during which alternative mechanisms of translation initiation prevail to express proteins required to cope with the stress, or to produce viral proteins. The diversity of noncanonical initiation mechanisms encompasses a broad range of strategies and cellular cofactors. Herein, we provide an overview and, whenever possible, a mechanistic understanding of the various noncanonical mechanisms of initiation used by cells and viruses. Despite many unanswered questions, recent advances have propelled our understanding of the scope, diversity, and mechanisms of alternative initiation.
Topics: Eukaryota; Internal Ribosome Entry Sites; Protein Biosynthesis; Protein Processing, Post-Translational; RNA Caps; RNA, Messenger
PubMed: 29959190
DOI: 10.1101/cshperspect.a032672 -
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 -
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