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Frontiers in Bioscience (Landmark... Oct 2023Metazoan adenosine-to-inosine (A-to-I) RNA editing is a highly conserved mechanism that diversifies the transcriptome by post-transcriptionally converting adenosine to... (Review)
Review
Metazoan adenosine-to-inosine (A-to-I) RNA editing is a highly conserved mechanism that diversifies the transcriptome by post-transcriptionally converting adenosine to inosine. Millions of editing sites have been identified in different species and, based on abnormal editing observed in various disorders, it is intuitive to conclude that RNA editing is both functional and adaptive. In this review, we propose the following major points: (1) "Function/functional" only represents a molecular/phenotypic consequence and is not necessarily connected to "adaptation/adaptive"; (2) Adaptive editing should be judged in the light of evolution and emphasize advantages of temporal-spatial flexibility; (3) Adaptive editing could, in theory, be extended from nonsynonymous sites to all potentially functional sites. This review seeks to conceptually bridge the gap between molecular biology and evolutionary biology and provide a more objective understanding on the biological functions and evolutionary significance of RNA editing.
Topics: Animals; RNA; RNA Editing; Adenosine; Inosine; Transcriptome
PubMed: 37919076
DOI: 10.31083/j.fbl2810256 -
Nature Communications Mar 2022RNA editing by adenosine deaminases changes the information encoded in the mRNA from its genomic blueprint. Editing of protein-coding sequences can introduce novel,...
RNA editing by adenosine deaminases changes the information encoded in the mRNA from its genomic blueprint. Editing of protein-coding sequences can introduce novel, functionally distinct, protein isoforms and diversify the proteome. The functional importance of a few recoding sites has been appreciated for decades. However, systematic methods to uncover these sites perform poorly, and the full repertoire of recoding in human and other mammals is unknown. Here we present a new detection approach, and analyze 9125 GTEx RNA-seq samples, to produce a highly-accurate atlas of 1517 editing sites within the coding region and their editing levels across human tissues. Single-cell RNA-seq data shows protein recoding contributes to the variability across cell subpopulations. Most highly edited sites are evolutionary conserved in non-primate mammals, attesting for adaptation. This comprehensive set can facilitate understanding of the role of recoding in human physiology and diseases.
Topics: Adenosine; Animals; Genome; Humans; Inosine; Mammals; RNA; RNA Editing
PubMed: 35246538
DOI: 10.1038/s41467-022-28841-4 -
Current Opinion in Structural Biology Aug 2021RNA undergoes extensive biochemical modification following transcription. In addition to RNA splicing, transcripts are processed by a suite of enzymes that alter the... (Review)
Review
RNA undergoes extensive biochemical modification following transcription. In addition to RNA splicing, transcripts are processed by a suite of enzymes that alter the chemical structure of different nucleobases. Broadly termed as 'RNA editing,' these modifications impart significant functional changes to translation, localization, and stability of individual transcripts within the cell. These changes are dynamic and required for a number of critical cellular processes, and dysregulation of these pathways is responsible for several disease states. Accurately detecting, measuring, and mapping different RNA modifications across the transcriptome is vital to understanding their broader functions as well as leveraging these events as diagnostic biomarkers. Here, we review recent advances in profiling several types of RNA modifications, with particular emphasis on adenosine-to-inosine (A-to-I) and N-methyladenosine (mA) RNA editing. We especially highlight approaches that utilize proteins to detect or enrich modified RNA transcripts before sequencing, and we summarize recent insights yielded from these techniques.
Topics: Adenosine; Inosine; RNA; RNA Editing; Transcriptome
PubMed: 33445115
DOI: 10.1016/j.sbi.2020.12.006 -
Harnessing methylation and AdoMet-utilising enzymes for selective modification in cascade reactions.Organic & Biomolecular Chemistry May 2021Enzyme-mediated methylation is a very important reaction in nature, yielding a wide range of modified natural products, diversifying small molecules and fine-tuning the... (Review)
Review
Enzyme-mediated methylation is a very important reaction in nature, yielding a wide range of modified natural products, diversifying small molecules and fine-tuning the activity of biomacromolecules. The field has attracted much attention over the recent years and interesting applications of the dedicated enzymes in biocatalysis and biomolecular labelling have emerged. In this review article, we summarise the concepts and recent advances in developing (chemo)-enzymatic cascades for selective methylation, alkylation and photocaging as tools to study biological methylation and as biotransformations to generate site-specifically alkylated products.
Topics: S-Adenosylmethionine
PubMed: 33949607
DOI: 10.1039/d1ob00354b -
Molecular Pharmaceutics Sep 2022Adenosine (ADO) is an endogenous metabolite with immense potential to be repurposed as an immunomodulatory therapeutic, as preclinical studies have demonstrated in...
Adenosine (ADO) is an endogenous metabolite with immense potential to be repurposed as an immunomodulatory therapeutic, as preclinical studies have demonstrated in models of epilepsy, acute respiratory distress syndrome, and traumatic brain injury, among others. The currently licensed products Adenocard and Adenoscan are formulated at 3 mg/mL of ADO for rapid bolus intravenous injection, but the systemic administration of the saline formulations for anti-inflammatory purposes is limited by the nucleoside's profound hemodynamic effects. Moreover, concentrations that can be attained in the airway or the brain through direct instillation or injection are limited by the volumes that can be accommodated in the anatomical space (<5 mL in humans) and the rapid elimination by enzymatic and transport mechanisms in the interstitium (half-life <5 s). As such, highly concentrated formulations of ADO are needed to attain pharmacologically relevant concentrations at sites of tissue injury. Herein, we report a previously uncharacterized crystalline form of ADO (rcADO) in which 6.7 mg/mL of the nucleoside is suspended in water. Importantly, the crystallinity is not diminished in a protein-rich environment, as evidenced by resuspending the crystals in albumin (15% w/v). To the best of our knowledge, this is the first report of crystalline ADO generated using a facile and organic solvent-free method aimed at localized drug delivery. The crystalline suspension may be suitable for developing ADO into injectable formulations for attaining high concentrations of the endogenous nucleoside in inflammatory locales.
Topics: Adenosine; Adenosine Kinase; Anti-Inflammatory Agents; Enzyme Inhibitors; Humans; Nucleosides
PubMed: 36001090
DOI: 10.1021/acs.molpharmaceut.2c00527 -
Plant Biotechnology Journal Jul 2019N6-methyladenosine (m6A) RNA methylation, one of the most pivotal internal modifications of RNA, is a conserved post-transcriptional mechanism to enrich and regulate... (Review)
Review
N6-methyladenosine (m6A) RNA methylation, one of the most pivotal internal modifications of RNA, is a conserved post-transcriptional mechanism to enrich and regulate genetic information in eukaryotes. The scope and function of this modification in plants has been an intense focus of study, especially in model plant systems. The characterization of plant m6A writers, erasers and readers, as well as the elucidation of their functions, is currently one of the most fascinating hotspots in plant biology research. The functional analysis of m6A in plants will be booming in the foreseeable future, which could contribute to crop genetic improvement through epitranscriptome manipulation. In this review, we systematically analysed and summarized recent advances in the understanding of the structure and composition of plant m6A regulatory machinery, and the biological functions of m6A in plant growth, development and stress response. Finally, our analysis showed that the evolutionary relationships between m6A modification components were highly conserved across the plant kingdom.
Topics: Adenosine; Evolution, Molecular; Methylation; Plants; RNA, Plant
PubMed: 31070865
DOI: 10.1111/pbi.13149 -
Molecules (Basel, Switzerland) Aug 2020The arbocyclic nucleosides aristeromycin and neplanocin have been studied as a source for new antiviral agents. A convenient synthesis of C-5'-truncated...
The arbocyclic nucleosides aristeromycin and neplanocin have been studied as a source for new antiviral agents. A convenient synthesis of C-5'-truncated 3-deaza-1',6'-isoneplanocin, which combines the features of antiviral candidates 5'-noraristeromycin and 3-deaza-1',6'-isoneplanocin is reported from (-)-cyclopentenone to give the two C-4' epimers of 5'-nor-3-deaza isoneplanocin. Antiviral assays showed activity against the JC virus (EC = 1.12 µM for (4')-; EC = 59.14 µM for (4')-) and inactivity of both compounds against several DNA and RNA viruses. Both compounds lacked cytotoxicity.
Topics: Adenosine; Antiviral Agents; Humans; JC Virus; RNA Viruses
PubMed: 32854369
DOI: 10.3390/molecules25173865 -
Genomics, Proteomics & Bioinformatics Jun 2018More than 100 modifications have been found in RNA. Analogous to epigenetic DNA methylation, epitranscriptomic modifications can be written, read, and erased by a... (Review)
Review
More than 100 modifications have been found in RNA. Analogous to epigenetic DNA methylation, epitranscriptomic modifications can be written, read, and erased by a complex network of proteins. Apart from N-methyladenosine (mA), N-methyladenosine (mA) has been found as a reversible modification in tRNA and mRNA. mA occurs at positions 9, 14, and 58 of tRNA, with mA58 being critical for tRNA stability. Other than the hundreds of mA sites in mRNA and long non-coding RNA transcripts, transcriptome-wide mapping of mA also identifies >20 mA sites in mitochondrial genes. mA in the coding region of mitochondrial transcripts can inhibit the translation of the corresponding proteins. In this review, we summarize the current understanding of mA in mRNA and tRNA, covering high-throughput sequencing methods developed for mA methylome, mA-related enzymes (writers and erasers), as well as its functions in mRNA and tRNA.
Topics: Adenosine; DNA Methylation; Epigenomics; Gene Expression Regulation; Humans; RNA, Messenger; RNA, Transfer
PubMed: 29908293
DOI: 10.1016/j.gpb.2018.03.003 -
Signal Transduction and Targeted Therapy Mar 2024Cellular metabolism is an intricate network satisfying bioenergetic and biosynthesis requirements of cells. Relevant studies have been constantly making inroads in our... (Review)
Review
Cellular metabolism is an intricate network satisfying bioenergetic and biosynthesis requirements of cells. Relevant studies have been constantly making inroads in our understanding of pathophysiology, and inspiring development of therapeutics. As a crucial component of epigenetics at post-transcription level, RNA modification significantly determines RNA fates, further affecting various biological processes and cellular phenotypes. To be noted, immunometabolism defines the metabolic alterations occur on immune cells in different stages and immunological contexts. In this review, we characterize the distribution features, modifying mechanisms and biological functions of 8 RNA modifications, including N6-methyladenosine (m6A), N6,2'-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), 5-methylcytosine (m5C), N4-acetylcytosine (ac4C), N7-methylguanosine (m7G), Pseudouridine (Ψ), adenosine-to-inosine (A-to-I) editing, which are relatively the most studied types. Then regulatory roles of these RNA modification on metabolism in diverse health and disease contexts are comprehensively described, categorized as glucose, lipid, amino acid, and mitochondrial metabolism. And we highlight the regulation of RNA modifications on immunometabolism, further influencing immune responses. Above all, we provide a thorough discussion about clinical implications of RNA modification in metabolism-targeted therapy and immunotherapy, progression of RNA modification-targeted agents, and its potential in RNA-targeted therapeutics. Eventually, we give legitimate perspectives for future researches in this field from methodological requirements, mechanistic insights, to therapeutic applications.
Topics: Immunotherapy; Adenosine; Amino Acids; Epigenesis, Genetic; RNA
PubMed: 38531882
DOI: 10.1038/s41392-024-01777-5 -
Trends in Genetics : TIG Dec 2016Eukaryotic mRNA undergoes chemical modification both at the 5' cap and internally. Among internal modifications, N-methyladensone (mA), by far the most abundant, is... (Review)
Review
Eukaryotic mRNA undergoes chemical modification both at the 5' cap and internally. Among internal modifications, N-methyladensone (mA), by far the most abundant, is present in all eukaryotes examined so far, including mammals, flies, plants, and yeast. mA modification has an essential role in diverse biological processes. Over the past few years, our knowledge relevant to the establishment and function of this modification has grown rapidly. In this review, we focus on technologies that have facilitated mA detection in mRNAs, the identification of mA methylation enzymes and binding proteins, and potential functions of the modification at the molecular level.
Topics: Adenosine; Animals; DNA Methylation; DNA-Binding Proteins; Eukaryotic Cells; Humans; RNA, Messenger
PubMed: 27793360
DOI: 10.1016/j.tig.2016.09.006