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Cold Spring Harbor Perspectives in... Feb 2019Nonsense-mediated mRNA decay (NMD) is arguably the best-studied eukaryotic messenger RNA (mRNA) surveillance pathway, yet fundamental questions concerning the molecular... (Review)
Review
Nonsense-mediated mRNA decay (NMD) is arguably the best-studied eukaryotic messenger RNA (mRNA) surveillance pathway, yet fundamental questions concerning the molecular mechanism of target RNA selection remain unsolved. Besides degrading defective mRNAs harboring premature termination codons (PTCs), NMD also targets many mRNAs encoding functional full-length proteins. Thus, NMD impacts on a cell's transcriptome and is implicated in a range of biological processes that affect a broad spectrum of cellular homeostasis. Here, we focus on the steps involved in the recognition of NMD targets and the activation of NMD. We summarize the accumulating evidence that tightly links NMD to translation termination and we further discuss the recruitment and activation of the mRNA degradation machinery and the regulation of this complex series of events. Finally, we review emerging ideas concerning the mechanistic details of NMD activation and the potential role of NMD as a general surveyor of translation efficacy.
Topics: Codon, Nonsense; Eukaryota; Nonsense Mediated mRNA Decay; Peptide Chain Termination, Translational; Protein Biosynthesis; RNA, Messenger
PubMed: 29891560
DOI: 10.1101/cshperspect.a032862 -
FASEB Journal : Official Publication of... Oct 2020
Topics: Animals; Humans; RNA, Messenger; Transfection; Vaccines, Synthetic; mRNA Vaccines
PubMed: 33373163
DOI: 10.1096/fj.202001874 -
Biomolecules Jan 2016RNA in cells is always associated with RNA-binding proteins that regulate all aspects of RNA metabolism including RNA splicing, export from the nucleus, RNA... (Review)
Review
RNA in cells is always associated with RNA-binding proteins that regulate all aspects of RNA metabolism including RNA splicing, export from the nucleus, RNA localization, mRNA turn-over as well as translation. Given their diverse functions, cells express a variety of RNA-binding proteins, which play important roles in the pathologies of a number of diseases. In this review we focus on the effect of alcohol on different RNA-binding proteins and their possible contribution to alcohol-related disorders, and discuss the role of these proteins in the development of neurological diseases and cancer. We further discuss the conventional methods and newer techniques that are employed to identify RNA-binding proteins.
Topics: Alcohol-Related Disorders; Alcohols; Binding Sites; Gene Expression Regulation; Humans; Neoplasms; Nervous System Diseases; RNA Splicing; RNA Stability; RNA, Messenger; RNA-Binding Proteins
PubMed: 26751491
DOI: 10.3390/biom6010004 -
RNA Biology Nov 2012mRNA vaccines combine desirable immunological properties with an outstanding safety profile and the unmet flexibility of genetic vaccines. Based on in situ protein... (Review)
Review
mRNA vaccines combine desirable immunological properties with an outstanding safety profile and the unmet flexibility of genetic vaccines. Based on in situ protein expression, mRNA vaccines are capable of inducing a balanced immune response comprising both cellular and humoral immunity while not subject to MHC haplotype restriction. In addition, mRNA is an intrinsically safe vector as it is a minimal and only transient carrier of information that does not interact with the genome. Because any protein can be expressed from mRNA without the need to adjust the production process, mRNA vaccines also offer maximum flexibility with respect to development. Taken together, mRNA presents a promising vector that may well become the basis of a game-changing vaccine technology platform. Here, we outline the current knowledge regarding different aspects that should be considered when developing an mRNA-based vaccine technology.
Topics: Adjuvants, Immunologic; Animals; Biological Transport; Gene Expression; Humans; RNA, Messenger; Vaccines, Synthetic
PubMed: 23064118
DOI: 10.4161/rna.22269 -
Biomaterials Science Nov 2017Gene therapy has long been held as having the potential to become a front line treatment for various genetic disorders. However, the direct delivery of nucleic acids to... (Review)
Review
Gene therapy has long been held as having the potential to become a front line treatment for various genetic disorders. However, the direct delivery of nucleic acids to correct a genetic disorder has numerous limitations owing to the inability of naked nucleic acids (DNA and RNA) to traverse the cell membrane. Recently, messenger RNA (mRNA) based delivery has become a more attractive alternative to DNA due to the relatively easier transfection process, higher efficiency and safety profile. As with all gene therapies, the central challenge that remains is the efficient delivery of nucleic acids intracellularly. This review presents the recent progress in mRNA delivery, focusing on comparing the advantages and limitations of non-viral based delivery vectors.
Topics: Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; RNA, Messenger; Transfection
PubMed: 29063914
DOI: 10.1039/c7bm00712d -
Critical Reviews in Eukaryotic Gene... 1999Within the nucleus, protein-encoding genes are transcribed into messenger RNA by RNA polymerase II. Messenger RNAs migrate to the cytoplasm, but before reaching their... (Review)
Review
Within the nucleus, protein-encoding genes are transcribed into messenger RNA by RNA polymerase II. Messenger RNAs migrate to the cytoplasm, but before reaching their final destination the primary transcripts must undergo a series of modifications that include 5'-capping, splicing, and 3'-cleavage/polyadenylation. Errors in these processing events can originate aberrant products that, if translated, would produce abnormal proteins. Therefore, it is not surprising that eukaryotes have evolved a surveillance mechanism that recognizes and rapidly degrades aberrant mRNAs. Recent experiments provide exciting insights into how proper mRNAs are distinguished and selected for export. Transcription by RNA polymerase II is directly coupled to pre-mRNA processing, and the mechanism that targets the processing machinery to the polymerase complex suggests a model for co-transcriptional proofreading. Furthermore, there is evidence that at least some mRNAs move randomly throughout the nucleus, presumably by free diffusion. In this light, retention of aberrant mRNAs by the transcription/processing machinery is crucial to prevent their diffusion to the nuclear pores and eventual translocation to the cytoplasm.
Topics: Animals; Biological Transport; Cell Nucleus; Humans; RNA, Messenger; Transcription, Genetic
PubMed: 10651238
DOI: 10.1615/critreveukargeneexpr.v9.i3-4.60 -
The AAPS Journal Oct 2023Delivery of RNA using nanomaterials has emerged as a new modality to expand therapeutic applications in biomedical research. However, the delivery of RNA presents unique... (Review)
Review
Delivery of RNA using nanomaterials has emerged as a new modality to expand therapeutic applications in biomedical research. However, the delivery of RNA presents unique challenges due to its susceptibility to degradation and the requirement for efficient intracellular delivery. The integration of nanotechnologies with RNA delivery has addressed many of these challenges. In this review, we discuss different strategies employed in the design and development of nanomaterials for RNA delivery. We also highlight recent advances in the pharmaceutical applications of RNA delivered via nanomaterials. Various nanomaterials, such as lipids, polymers, peptides, nucleic acids, and inorganic nanomaterials, have been utilized for delivering functional RNAs, including messenger RNA (mRNA), small interfering RNA, single guide RNA, and microRNA. Furthermore, the utilization of nanomaterials has expanded the applications of functional RNA as active pharmaceutical ingredients. For instance, the delivery of antigen-encoding mRNA using nanomaterials enables the transient expression of vaccine antigens, leading to immunogenicity and prevention against infectious diseases. Additionally, nanomaterial-mediated RNA delivery has been investigated for engineering cells to express exogenous functional proteins. Nanomaterials have also been employed for co-delivering single guide RNA and mRNA to facilitate gene editing of genetic diseases. Apart from the progress made in RNA medicine, we discuss the current challenges and future directions in this field.
Topics: Nanomedicine; Nanotechnology; Pharmaceutical Preparations; RNA, Small Interfering; RNA, Messenger
PubMed: 37784005
DOI: 10.1208/s12248-023-00860-z -
Nature May 2011Gene expression is a multistep process that involves the transcription, translation and turnover of messenger RNAs and proteins. Although it is one of the most...
Gene expression is a multistep process that involves the transcription, translation and turnover of messenger RNAs and proteins. Although it is one of the most fundamental processes of life, the entire cascade has never been quantified on a genome-wide scale. Here we simultaneously measured absolute mRNA and protein abundance and turnover by parallel metabolic pulse labelling for more than 5,000 genes in mammalian cells. Whereas mRNA and protein levels correlated better than previously thought, corresponding half-lives showed no correlation. Using a quantitative model we have obtained the first genome-scale prediction of synthesis rates of mRNAs and proteins. We find that the cellular abundance of proteins is predominantly controlled at the level of translation. Genes with similar combinations of mRNA and protein stability shared functional properties, indicating that half-lives evolved under energetic and dynamic constraints. Quantitative information about all stages of gene expression provides a rich resource and helps to provide a greater understanding of the underlying design principles.
Topics: Animals; Gene Expression Profiling; Gene Expression Regulation; Half-Life; Mammals; Mice; Models, Genetic; NIH 3T3 Cells; Protein Biosynthesis; Proteins; RNA, Messenger; Reproducibility of Results; Staining and Labeling
PubMed: 21593866
DOI: 10.1038/nature10098 -
Expert Reviews in Molecular Medicine Apr 2024Despite gene-expression profiling being one of the most common methods to evaluate molecular dysregulation in tissues, the utilization of cell-free messenger RNA... (Review)
Review
Despite gene-expression profiling being one of the most common methods to evaluate molecular dysregulation in tissues, the utilization of cell-free messenger RNA (cf-mRNA) as a blood-based non-invasive biomarker analyte has been limited compared to other RNA classes. Recent advancements in low-input RNA-sequencing and normalization techniques, however, have enabled characterization as well as accurate quantification of cf-mRNAs allowing direct pathological insights. The molecular profile of the cell-free transcriptome in multiple diseases has subsequently been characterized including, prenatal diseases, neurological disorders, liver diseases and cancers suggesting this biological compartment may serve as a disease agnostic platform. With mRNAs packaged in a myriad of extracellular vesicles and particles, these signals may be used to develop clinically actionable, non-invasive disease biomarkers. Here, we summarize the recent scientific developments of extracellular mRNA, biology of extracellular mRNA carriers, clinical utility of cf-mRNA as disease biomarkers, as well as proposed functions in cell and tissue pathophysiology.
Topics: Animals; Humans; Biomarkers; Cell-Free Nucleic Acids; Extracellular Vesicles; RNA, Messenger; Transcriptome
PubMed: 38682644
DOI: 10.1017/erm.2024.12 -
Journal of Medical Genetics Sep 1972
Review
Topics: Animals; Base Sequence; Cattle; Cell-Free System; Centrifugation, Zonal; Chickens; Ducks; Electrophoresis, Polyacrylamide Gel; Gene Frequency; Genetic Diseases, Inborn; Globins; Guinea Pigs; Humans; Mice; Molecular Weight; Nucleic Acid Hybridization; Nucleotides; Phosphorus Isotopes; RNA, Messenger; Rabbits; Reticulocytes
PubMed: 4562434
DOI: 10.1136/jmg.9.3.348