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Pharmacology 2023The most prevalent kind of RNA methylation modification existing in eukaryotes is N6-methyladenosine (m6A), which is a reversible type of posttranscriptional... (Review)
Review
BACKGROUND
The most prevalent kind of RNA methylation modification existing in eukaryotes is N6-methyladenosine (m6A), which is a reversible type of posttranscriptional modification.
SUMMARY
Many studies have reported that m6A participates in cell differentiation, self-renewal, invasion, and apoptosis by modifying protein synthesis. Furthermore, m6A modification is also involved in disease progression and pulmonary vascular remodeling in pulmonary hypertension. However, very few researchers have investigated the effect of m6A modifications on pulmonary hypertension.
KEY MESSAGES
Here, we have reviewed the latest research advances in the field of m6A RNA methylation in pulmonary hypertension and explored its regulatory role in pulmonary hypertension development and progression.
Topics: Humans; Hypertension, Pulmonary; Adenosine; Apoptosis; RNA
PubMed: 37742623
DOI: 10.1159/000533588 -
Annual Review of Biochemistry Jun 2023Over the past decade, mRNA modifications have emerged as important regulators of gene expression control in cells. Fueled in large part by the development of tools for... (Review)
Review
Over the past decade, mRNA modifications have emerged as important regulators of gene expression control in cells. Fueled in large part by the development of tools for detecting RNA modifications transcriptome wide, researchers have uncovered a diverse epitranscriptome that serves as an additional layer of gene regulation beyond simple RNA sequence. Here, we review the proteins that write, read, and erase these marks, with a particular focus on the most abundant internal modification, -methyladenosine (mA). We first describe the discovery of the key enzymes that deposit and remove mA and other modifications and discuss how our understanding of these proteins has shaped our views of modification dynamics. We then review current models for the function of mA reader proteins and how our knowledge of these proteins has evolved. Finally, we highlight important future directions for the field and discuss key questions that remain unanswered.
Topics: RNA, Messenger; Adenosine; Gene Expression Regulation; Proteins; Transcriptome
PubMed: 37068770
DOI: 10.1146/annurev-biochem-052521-035330 -
Current Heart Failure Reports Oct 2020Post-transcriptional modifications are key regulators of gene expression that allow the cell to respond to environmental stimuli. The most abundant internal mRNA... (Review)
Review
PURPOSE OF REVIEW
Post-transcriptional modifications are key regulators of gene expression that allow the cell to respond to environmental stimuli. The most abundant internal mRNA modification is N6-methyladenosine (mA), which has been shown to be involved in the regulation of RNA splicing, localization, translation, and decay. It has also been implicated in a wide range of diseases, and here, we review recent evidence of mA's involvement in cardiac pathologies and processes.
RECENT FINDINGS
Studies have primarily relied on gain and loss of function models for the enzymes responsible for adding and removing the mA modification. Results have revealed a multifaceted role for mA in the heart's response to myocardial infarction, pressure overload, and ischemia/reperfusion injuries. Genome-wide analyses of mRNAs that are differentially methylated during cardiac stress have highlighted the importance of mA in regulating the translation of specific categories of transcripts implicated in pathways such as calcium handling, cell growth, autophagy, and adrenergic signaling in cardiomyocytes. Regulation of gene expression by mA is critical for cardiomyocyte homeostasis and stress responses, suggesting a key role for this modification in cardiac pathophysiology.
Topics: Adenosine; Epigenesis, Genetic; Genome-Wide Association Study; Heart Failure; Humans; RNA, Messenger; Signal Transduction
PubMed: 32813261
DOI: 10.1007/s11897-020-00473-z -
Redox Biology Jan 2020Chemical modifications of DNA and RNA regulate genome functions or trigger mutagenesis resulting in aging or cancer. Oxidations of macromolecules, including DNA, are... (Review)
Review
Chemical modifications of DNA and RNA regulate genome functions or trigger mutagenesis resulting in aging or cancer. Oxidations of macromolecules, including DNA, are common reactions in biological systems and often part of regulatory circuits rather than accidental events. DNA alterations are particularly relevant since the unique role of nuclear and mitochondrial genome is coding enduring and inheritable information. Therefore, an alteration in DNA may represent a relevant problem given its transmission to daughter cells. At the same time, the regulation of gene expression allows cells to continuously adapt to the environmental changes that occur throughout the life of the organism to ultimately maintain cellular homeostasis. Here we review the multiple ways that lead to DNA oxidation and the regulation of mechanisms activated by cells to repair this damage. Moreover, we present the recent evidence suggesting that DNA damage caused by physiological metabolism acts as epigenetic signal for regulation of gene expression. In particular, the predisposition of guanine to oxidation might reflect an adaptation to improve the genome plasticity to redox changes.
Topics: DNA Damage; DNA Repair; Epigenesis, Genetic; Guanosine; Oxidation-Reduction
PubMed: 31926624
DOI: 10.1016/j.redox.2019.101398 -
BioMed Research International 2020Equilibrative nucleoside transporter 2 (ENT2) is a bidirectional transporter embedded in the biological membrane and is ubiquitously found in most tissue and cell types.... (Review)
Review
Equilibrative nucleoside transporter 2 (ENT2) is a bidirectional transporter embedded in the biological membrane and is ubiquitously found in most tissue and cell types. ENT2 mediates the uptake of purine and pyrimidine nucleosides and nucleobase besides transporting a variety of nucleoside-derived drugs, mostly in anticancer therapy. Since high expression of ENT2 has been correlated with advanced stages of different types of cancers, consequently, this has gained significant interest in the role of ENT2 as a potential therapeutic target. Furthermore, ENT2 plays critical roles in signaling pathway and cell cycle progression. Therefore, elucidating the physiological roles of ENT2 and its properties may contribute to a better understanding of ENT2 roles beyond their transportation mechanism. This review is aimed at highlighting the main roles of ENT2 and at providing a brief update on the recent research.
Topics: Adenosine; Animals; Antineoplastic Agents; Biological Transport; Biomarkers; Cell Cycle; Cell Line, Tumor; Cell Membrane; Equilibrative-Nucleoside Transporter 2; Glycosylation; Humans; Mice; Neoplasms; Nucleosides; Rabbits; Rats; Signal Transduction
PubMed: 33344638
DOI: 10.1155/2020/5197626 -
International Journal of Molecular... Jan 2023The purine signaling system is represented by purine and pyrimidine nucleotides and nucleosides that exert their effects through the adenosine, P2X and P2Y receptor... (Review)
Review
The purine signaling system is represented by purine and pyrimidine nucleotides and nucleosides that exert their effects through the adenosine, P2X and P2Y receptor families. It is known that, under physiological conditions, P2 receptors play only a minor role in modulating the functions of cells and systems; however, their role significantly increases under some pathophysiological conditions, such as stress, ischemia or hypothermia, when they can play a dominant role as a signaling molecule. The diversity of P2 receptors and their wide distribution in the body make them very attractive as a target for the pharmacological action of drugs with a new mechanism of action. The review is devoted to the involvement of P2 signaling in the development of pathologies associated with a loss of muscle mass. The contribution of adenosine triphosphate (ATP) as a signal molecule in the pathogenesis of a number of muscular dystrophies (Duchenne, Becker and limb girdle muscular dystrophy 2B) is considered. To understand the processes involving the purinergic system, the role of the ATP and P2 receptors in several models associated with skeletal muscle degradation is also discussed.
Topics: Humans; Receptors, Purinergic P2; Adenosine Triphosphate; Muscular Dystrophies; Adenosine; Signal Transduction
PubMed: 36675094
DOI: 10.3390/ijms24021587 -
Natural Product Reports Sep 2023Covering: from 2000 up to the very early part of 2023-Adenosyl-L-methionine (SAM) is a naturally occurring trialkyl sulfonium molecule that is typically associated with... (Review)
Review
Covering: from 2000 up to the very early part of 2023-Adenosyl-L-methionine (SAM) is a naturally occurring trialkyl sulfonium molecule that is typically associated with biological methyltransfer reactions. However, SAM is also known to donate methylene, aminocarboxypropyl, adenosyl and amino moieties during natural product biosynthetic reactions. The reaction scope is further expanded as SAM itself can be modified prior to the group transfer such that a SAM-derived carboxymethyl or aminopropyl moiety can also be transferred. Moreover, the sulfonium cation in SAM has itself been found to be critical for several other enzymatic transformations. Thus, while many SAM-dependent enzymes are characterized by a methyltransferase fold, not all of them are necessarily methyltransferases. Furthermore, other SAM-dependent enzymes do not possess such a structural feature suggesting diversification along different evolutionary lineages. Despite the biological versatility of SAM, it nevertheless parallels the chemistry of sulfonium compounds used in organic synthesis. The question thus becomes how enzymes catalyze distinct transformations subtle differences in their active sites. This review summarizes recent advances in the discovery of novel SAM utilizing enzymes that rely on Lewis acid/base chemistry as opposed to radical mechanisms of catalysis. The examples are categorized based on the presence of a methyltransferase fold and the role played by SAM within the context of known sulfonium chemistry.
Topics: S-Adenosylmethionine; Methyltransferases; Catalysis
PubMed: 36891755
DOI: 10.1039/d2np00086e -
Journal of the American Chemical Society Sep 2021The hypothesis that life on Earth may have started with a heterogeneous nucleic acid genetic system including both RNA and DNA has attracted broad interest. The recent...
The hypothesis that life on Earth may have started with a heterogeneous nucleic acid genetic system including both RNA and DNA has attracted broad interest. The recent finding that two RNA subunits (cytidine, C, and uridine, U) and two DNA subunits (deoxyadenosine, dA, and deoxyinosine, dI) can be coproduced in the same reaction network, compatible with a consistent geological scenario, supports this theory. However, a prebiotically plausible synthesis of the missing units (purine ribonucleosides and pyrimidine deoxyribonucleosides) in a unified reaction network remains elusive. Herein, we disclose a strictly stereoselective and furanosyl-selective synthesis of purine ribonucleosides (adenosine, A, and inosine, I) and purine deoxynucleosides (dA and dI), alongside one another, via a key photochemical reaction of thioanhydroadenosine with sulfite in alkaline solution (pH 8-10). Mechanistic studies suggest an unexpected recombination of sulfite and nucleoside alkyl radicals underpins the formation of the ribo C2'-O bond. The coproduction of A, I, dA, and dI from a common intermediate, and under conditions likely to have prevailed in at least some primordial locales, is suggestive of the potential coexistence of RNA and DNA building blocks at the dawn of life.
Topics: Adenosine; Deoxyribonucleosides; Evolution, Chemical; Hydrogen-Ion Concentration; Models, Chemical; Purine Nucleosides; Ribonucleosides; Sulfites; Ultraviolet Rays
PubMed: 34469129
DOI: 10.1021/jacs.1c07403 -
The Journal of Thoracic and... Aug 2019
Topics: Clopidogrel; Coronary Artery Bypass; Ticagrelor
PubMed: 30501944
DOI: 10.1016/j.jtcvs.2018.10.095 -
ELife Sep 2022can persist over extended times within their host cell and thereby establish chronic infections. One of the major inducers of chlamydial persistence is interferon-gamma...
can persist over extended times within their host cell and thereby establish chronic infections. One of the major inducers of chlamydial persistence is interferon-gamma (IFN-γ) released by immune cells as a mechanism of immune defence. IFN-γ activates the catabolic depletion of L-tryptophan (Trp) via indoleamine-2,3-dioxygenase (IDO), resulting in persistent . Here, we show that IFN-γ induces the downregulation of c-Myc, the key regulator of host cell metabolism, in a STAT1-dependent manner. Expression of c-Myc rescued from IFN-γ-induced persistence in cell lines and human fallopian tube organoids. Trp concentrations control c-Myc levels most likely via the PI3K-GSK3β axis. Unbiased metabolic analysis revealed that infection reprograms the host cell tricarboxylic acid (TCA) cycle to support pyrimidine biosynthesis. Addition of TCA cycle intermediates or pyrimidine/purine nucleosides to infected cells rescued from IFN-γ-induced persistence. Thus, our results challenge the longstanding hypothesis of Trp depletion through IDO as the major mechanism of IFN-γ-induced metabolic immune defence and significantly extends the understanding of the role of IFN-γ as a broad modulator of host cell metabolism.
Topics: Cell Line; Chlamydia trachomatis; Female; Glycogen Synthase Kinase 3 beta; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Interferon-gamma; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-myc; Purine Nucleosides; Pyrimidines; Tricarboxylic Acids; Tryptophan
PubMed: 36155135
DOI: 10.7554/eLife.76721