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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 -
International Journal of Biological... 2021Circular RNA (circRNA) is a type of covalently closed and endogenous non-coding RNA (ncRNA) with tissue- and cell-specific expression patterns generated by a... (Review)
Review
Circular RNA (circRNA) is a type of covalently closed and endogenous non-coding RNA (ncRNA) with tissue- and cell-specific expression patterns generated by a non-canonical splicing event. Previous reports have indicated that circRNAs exert their functions in different ways, thereby participating in various pathophysiological processes. -methyladenosine (mA) methylation occurs in the -position, which is the most abundant and conserved internal transcriptional modification in eukaryotes, including mRNA and ncRNAs. Accumulating evidences confirm that mA modification also exists in the circRNA and greatly affects the biological functions of circRNA. Their dysregulated expression can be a cause of various pathophysiological processes, such as spermatogenesis, myoblast differentiation, cancer, cardiovascular disease, mental illness and so on. Understanding the role of mA-modified circRNAs in pathophysiological processes may contribute to better understanding the physiological mechanisms and develop new biomarkers. This review summarizes the regulatory mechanism of mA modification on circRNA metabolism and the role of mA-modified circRNAs in pathophysiological processes. This article may pave the way for a better understanding of the role of epigenetically modified circRNAs in pathophysiological process.
Topics: Adenosine; Animals; DNA Methylation; Disease Progression; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; RNA, Circular
PubMed: 34239354
DOI: 10.7150/ijbs.60131 -
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 -
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 -
Biomedicine & Pharmacotherapy =... Sep 2023Cordycepin (with a molecular formula of CHNO), a natural adenosine isolated from Cordyceps militaris, has an important regulatory effect on skeletal muscle remodelling...
Cordycepin (with a molecular formula of CHNO), a natural adenosine isolated from Cordyceps militaris, has an important regulatory effect on skeletal muscle remodelling and quality maintenance. The aim of this study was to investigate the effect of cordycepin on myoblast differentiation and explore the underlying molecular mechanisms of this effect. Our results showed that cordycepin inhibited myogenesis by downregulating myogenic differentiation (MyoD) and myogenin (MyoG), preserved undifferentiated reserve cell pools by upregulating myogenic factor 5 (Myf5) and retinoblastoma-like protein p130 (p130), and enhanced energy reserves by decreasing intracellular reactive oxygen species (ROS) and enhancing mitochondrial membrane potential, mitochondrial mass, and ATP content. The effect of cordycepin on myogenesis was associated with increased phosphorylation of extracellular signal-regulated kinase 1/2 (p-ERK1/2). PD98059 (a specific inhibitor of p-ERK1/2) attenuated the inhibitory effect of cordycepin on C2C12 differentiation. The present study reveals that cordycepin inhibits myogenesis through ERK1/2 MAPK signalling activation accompanied by an increase in skeletal muscle energy reserves and improving skeletal muscle oxidative stress, which may have implications for its further application for the prevention and treatment of degenerative muscle diseases caused by the depletion of depleted muscle stem cells.
Topics: MAP Kinase Signaling System; Cell Differentiation; Deoxyadenosines; Muscle Development
PubMed: 37453196
DOI: 10.1016/j.biopha.2023.115163 -
Journal of Experimental & Clinical... Apr 2021The N6-methyladenosine (m6A) modification is a dynamic and reversible epigenetic modification, which is co-transcriptionally deposited by a methyltransferase complex,... (Review)
Review
The N6-methyladenosine (m6A) modification is a dynamic and reversible epigenetic modification, which is co-transcriptionally deposited by a methyltransferase complex, removed by a demethylase, and recognized by reader proteins. Mechanistically, m6A modification regulates the expression levels of mRNA and nocoding RNA by modulating the fate of modified RNA molecules, such as RNA splicing, nuclear transport, translation, and stability. Several studies have shown that m6A modification is dysregulated in the progression of multiple diseases, especially human tumors. We emphasized that the dysregulation of m6A modification affects different signal transduction pathways and involves in the biological processes underlying tumor cell proliferation, apoptosis, invasion and migration, and metabolic reprogramming, and discuss the effects on different cancer treatment.
Topics: Adenosine; Disease Progression; Humans; Neoplasms; Signal Transduction
PubMed: 33926508
DOI: 10.1186/s13046-021-01952-4 -
Journal of Hematology & Oncology Apr 2020N-methyladenosine (mA) is a well-known post-transcriptional modification that is the most common type of methylation in eukaryotic mRNAs. The regulation of mA is dynamic... (Review)
Review
N-methyladenosine (mA) is a well-known post-transcriptional modification that is the most common type of methylation in eukaryotic mRNAs. The regulation of mA is dynamic and reversible, which is erected by mA methyltransferases ("writers") and removed by mA demethylases ("erasers"). Notably, the effects on targeted mRNAs resulted by mA predominantly depend on the functions of different mA-binding proteins ("readers") including YT521-B homology (YTH) domain family, heterogeneous nuclear ribonucleoproteins (HNRNPs), and insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs). Indeed, mA readers not only participate in multiple procedures of RNA metabolism, but also are involved in a variety of biological processes. In this review, we summarized the specific functions and underlying mechanisms of mA-binding proteins in tumorigenesis, hematopoiesis, virus replication, immune response, and adipogenesis.
Topics: Adenosine; Animals; Epigenesis, Genetic; Hematopoiesis; Humans; Neoplasms; Protein Binding; Proteins; RNA Processing, Post-Transcriptional; RNA, Messenger; Virus Diseases; Virus Physiological Phenomena; Viruses
PubMed: 32276589
DOI: 10.1186/s13045-020-00872-8 -
American Journal of Physiology. Cell... Nov 2022Adenosine deaminases acting on RNAs convert adenosines (A) to inosines (I) in structured or double-stranded RNAs. In mammals, this process is widespread. In the human... (Review)
Review
Adenosine deaminases acting on RNAs convert adenosines (A) to inosines (I) in structured or double-stranded RNAs. In mammals, this process is widespread. In the human transcriptome, more than a million different sites have been identified that undergo an ADAR-mediated A-to-I exchange Inosines have an altered base pairing potential due to the missing amino group when compared to the original adenosine. Consequently, inosines prefer to base pair with cytosines but can also base pair with uracil or adenine. This altered base pairing potential not only affects protein decoding at the ribosome but also influences the folding of RNAs and the proteins that can associate with it. Consequently, an A to I exchange can also affect RNA processing and turnover (Nishikura K. 79: 321-349, 2010; Brümmer A, Yang Y, Chan TW, Xiao X. 8: 1255, 2017). All of these events will interfere with gene expression and therefore, can also affect cellular and organismic physiology. As double-stranded RNAs are a hallmark of viral pathogens RNA-editing not only affects RNA-processing, coding, and gene expression but also controls the antiviral response to double-stranded RNAs. Most interestingly, recent advances in our understanding of ADAR enzymes reveal multiple layers of regulation by which ADARs can control antiviral programs. In this review, we focus on the recoding of mRNAs where the altered translation products lead to physiological changes. We also address recent advances in our understanding of the multiple layers of antiviral responses and innate immune modulations mediated by ADAR1.
Topics: Animals; Humans; RNA Editing; RNA-Binding Proteins; Inosine; RNA, Double-Stranded; Adenosine; RNA, Viral; Mammals; Antiviral Agents
PubMed: 36036447
DOI: 10.1152/ajpcell.00191.2022