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Journal of Hematology & Oncology May 2022N-methylguanosine (m7G), one of the most prevalent RNA modifications, has recently attracted significant attention. The m7G modification actively participates in... (Review)
Review
N-methylguanosine (m7G), one of the most prevalent RNA modifications, has recently attracted significant attention. The m7G modification actively participates in biological and pathological functions by affecting the metabolism of various RNA molecules, including messenger RNA, ribosomal RNA, microRNA, and transfer RNA. Increasing evidence indicates a critical role for m7G in human disease development, especially cancer, and aberrant m7G levels are closely associated with tumorigenesis and progression via regulation of the expression of multiple oncogenes and tumor suppressor genes. Currently, the underlying molecular mechanisms of m7G modification in cancer are not comprehensively understood. Here, we review the current knowledge regarding the potential function of m7G modifications in cancer and discuss future m7G-related diagnostic and therapeutic strategies.
Topics: Guanosine; Humans; MicroRNAs; Neoplasms; RNA, Messenger
PubMed: 35590385
DOI: 10.1186/s13045-022-01285-5 -
Molecular Cell Jun 20197-methylguanosine (m7G) is present at mRNA caps and at defined internal positions within tRNAs and rRNAs. However, its detection within low-abundance mRNAs and microRNAs...
7-methylguanosine (m7G) is present at mRNA caps and at defined internal positions within tRNAs and rRNAs. However, its detection within low-abundance mRNAs and microRNAs (miRNAs) has been hampered by a lack of sensitive detection strategies. Here, we adapt a chemical reactivity assay to detect internal m7G in miRNAs. Using this technique (Borohydride Reduction sequencing [BoRed-seq]) alongside RNA immunoprecipitation, we identify m7G within a subset of miRNAs that inhibit cell migration. We show that the METTL1 methyltransferase mediates m7G methylation within miRNAs and that this enzyme regulates cell migration via its catalytic activity. Using refined mass spectrometry methods, we map m7G to a single guanosine within the let-7e-5p miRNA. We show that METTL1-mediated methylation augments let-7 miRNA processing by disrupting an inhibitory secondary structure within the primary miRNA transcript (pri-miRNA). These results identify METTL1-dependent N7-methylation of guanosine as a new RNA modification pathway that regulates miRNA structure, biogenesis, and cell migration.
Topics: A549 Cells; Base Sequence; Biological Assay; Caco-2 Cells; Cell Movement; Cell Proliferation; Guanosine; HEK293 Cells; Humans; Methylation; Methyltransferases; MicroRNAs; Nucleic Acid Conformation; RNA Processing, Post-Transcriptional
PubMed: 31031083
DOI: 10.1016/j.molcel.2019.03.040 -
Purinergic Signalling Sep 2016Guanosine is a purine nucleoside thought to have neuroprotective properties. It is released in the brain under physiological conditions and even more during pathological... (Review)
Review
Guanosine is a purine nucleoside thought to have neuroprotective properties. It is released in the brain under physiological conditions and even more during pathological events, reducing neuroinflammation, oxidative stress, and excitotoxicity, as well as exerting trophic effects in neuronal and glial cells. In agreement, guanosine was shown to be protective in several in vitro and/or in vivo experimental models of central nervous system (CNS) diseases including ischemic stroke, Alzheimer's disease, Parkinson's disease, spinal cord injury, nociception, and depression. The mechanisms underlying the neurobiological properties of guanosine seem to involve the activation of several intracellular signaling pathways and a close interaction with the adenosinergic system, with a consequent stimulation of neuroprotective and regenerative processes in the CNS. Within this context, the present review will provide an overview of the current literature on the effects of guanosine in the CNS. The elucidation of the complex signaling events underlying the biochemical and cellular effects of this nucleoside may further establish guanosine as a potential therapeutic target for the treatment of several neuropathologies.
Topics: Animals; Central Nervous System; Central Nervous System Diseases; Guanosine; Humans
PubMed: 27002712
DOI: 10.1007/s11302-016-9509-4 -
Molecular Cell Jul 2018tRNAs are subject to numerous modifications, including methylation. Mutations in the human N-methylguanosine (mG) methyltransferase complex METTL1/WDR4 cause primordial...
tRNAs are subject to numerous modifications, including methylation. Mutations in the human N-methylguanosine (mG) methyltransferase complex METTL1/WDR4 cause primordial dwarfism and brain malformation, yet the molecular and cellular function in mammals is not well understood. We developed mG methylated tRNA immunoprecipitation sequencing (MeRIP-seq) and tRNA reduction and cleavage sequencing (TRAC-seq) to reveal the mG tRNA methylome in mouse embryonic stem cells (mESCs). A subset of 22 tRNAs is modified at a "RAGGU" motif within the variable loop. We observe increased ribosome occupancy at the corresponding codons in Mettl1 knockout mESCs, implying widespread effects on tRNA function, ribosome pausing, and mRNA translation. Translation of cell cycle genes and those associated with brain abnormalities is particularly affected. Mettl1 or Wdr4 knockout mESCs display defective self-renewal and neural differentiation. Our study uncovers the complexity of the mammalian mG tRNA methylome and highlights its essential role in ESCs with links to human disease.
Topics: Animals; Base Sequence; Cell Differentiation; Cell Line; Cell Self Renewal; Embryonic Stem Cells; GTP-Binding Proteins; Guanosine; Humans; Methylation; Methyltransferases; Mice; Mouse Embryonic Stem Cells; RNA Processing, Post-Transcriptional; RNA, Transfer
PubMed: 29983320
DOI: 10.1016/j.molcel.2018.06.001 -
Naunyn-Schmiedeberg's Archives of... Jul 2020The effects of 100 μM of 3',5'-cGMP, cAMP, cCMP, and cUMP as well as of the corresponding membrane-permeant acetoxymethyl esters on anti-CD3-antibody (OKT3)-induced... (Comparative Study)
Comparative Study
The effects of 100 μM of 3',5'-cGMP, cAMP, cCMP, and cUMP as well as of the corresponding membrane-permeant acetoxymethyl esters on anti-CD3-antibody (OKT3)-induced IL-2 production of HuT-78 cutaneous T cell lymphoma (Sézary lymphoma) cells were analyzed. Only 3',5'-cGMP significantly reduced IL-2 production. Flow cytometric analysis of apoptotic (propidium iodide/annexin V staining) and anti-proliferative (CFSE staining) effects revealed that 3',5'-cGMP concentrations > 50 μM strongly inhibited proliferation and promoted apoptosis of HuT-78 cells (cultured in the presence of αCD3 antibody). Similar effects were observed for the positional isomer 2',3'-cGMP and for 2',-GMP, 3'-GMP, 5'-GMP, and guanosine. By contrast, guanosine and guanosine-derived nucleotides had no cytotoxic effect on peripheral blood mononuclear cells (PBMCs) or acute lymphocytic leukemia (ALL) xenograft cells. The anti-proliferative and apoptotic effects of guanosine and guanosine-derived compounds on HuT-78 cells were completely eliminated by the nucleoside transport inhibitor NBMPR (S-(4-Nitrobenzyl)-6-thioinosine). By contrast, the ecto-phosphodiesterase inhibitor DPSPX (1,3-dipropyl-8-sulfophenylxanthine) and the CD73 ecto-5'-nucleotidase inhibitor AMP-CP (adenosine 5'-(α,β-methylene)diphosphate) were not protective. We hypothesize that HuT-78 cells metabolize guanosine-derived nucleotides to guanosine by yet unknown mechanisms. Guanosine then enters the cells by an NBMPR-sensitive nucleoside transporter and exerts cytotoxic effects. This transporter may be ENT1 because NBMPR counteracted guanosine cytotoxicity in HuT-78 cells with nanomolar efficacy (IC of 25-30 nM). Future studies should further clarify the mechanism of the observed effects and address the question, whether guanosine or guanosine-derived nucleotides may serve as adjuvants in the therapy of cancers that express appropriate nucleoside transporters and are sensitive to established nucleoside-derived cytostatic drugs.
Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Guanosine; Humans; Inhibitory Concentration 50; Leukocytes, Mononuclear; Lymphoma, T-Cell; Nucleoside Transport Proteins; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Xenograft Model Antitumor Assays
PubMed: 32313990
DOI: 10.1007/s00210-020-01864-8 -
International Journal of Molecular... Dec 2018More than 90 different modified nucleosides have been identified in tRNA. Among the tRNA modifications, the 7-methylguanosine (m⁷G) modification is found widely in... (Review)
Review
More than 90 different modified nucleosides have been identified in tRNA. Among the tRNA modifications, the 7-methylguanosine (m⁷G) modification is found widely in eubacteria, eukaryotes, and a few archaea. In most cases, the m⁷G modification occurs at position 46 in the variable region and is a product of tRNA (m⁷G46) methyltransferase. The m⁷G46 modification forms a tertiary base pair with C13-G22, and stabilizes the tRNA structure. A reaction mechanism for eubacterial tRNA m⁷G methyltransferase has been proposed based on the results of biochemical, bioinformatic, and structural studies. However, an experimentally determined mechanism of methyl-transfer remains to be ascertained. The physiological functions of m⁷G46 in tRNA have started to be determined over the past decade. For example, tRNA m⁷G46 or tRNA (m⁷G46) methyltransferase controls the amount of other tRNA modifications in thermophilic bacteria, contributes to the pathogenic infectivity, and is also associated with several diseases. In this review, information of tRNA m⁷G modifications and tRNA m⁷G methyltransferases is summarized and the differences in reaction mechanism between tRNA m⁷G methyltransferase and rRNA or mRNA m⁷G methylation enzyme are discussed.
Topics: Animals; Bacteria; Bacterial Proteins; Guanosine; Humans; RNA Processing, Post-Transcriptional; RNA, Bacterial; RNA, Transfer; tRNA Methyltransferases
PubMed: 30562954
DOI: 10.3390/ijms19124080 -
The Biochemical Journal Jan 2014The 7mG (7-methylguanosine cap) formed on mRNA is fundamental to eukaryotic gene expression. Protein complexes recruited to 7mG mediate key processing events throughout... (Review)
Review
The 7mG (7-methylguanosine cap) formed on mRNA is fundamental to eukaryotic gene expression. Protein complexes recruited to 7mG mediate key processing events throughout the lifetime of the transcript. One of the most important mediators of 7mG functions is CBC (cap-binding complex). CBC has a key role in several gene expression mechanisms, including transcription, splicing, transcript export and translation. Gene expression can be regulated by signalling pathways which influence CBC function. The aim of the present review is to discuss the mechanisms by which CBC mediates and co-ordinates multiple gene expression events.
Topics: Animals; Gene Expression Regulation; Guanosine; Humans; Nuclear Cap-Binding Protein Complex; RNA Cap-Binding Proteins; RNA Caps; RNA, Messenger; Signal Transduction
PubMed: 24354960
DOI: 10.1042/BJ20131214 -
Bioorganic Chemistry Aug 2012Pyrrolopyrimidine containing compounds, also known as 7-deazapurines, are a collection of purine-based metabolites that have been isolated from a variety of biological... (Review)
Review
Pyrrolopyrimidine containing compounds, also known as 7-deazapurines, are a collection of purine-based metabolites that have been isolated from a variety of biological sources and have diverse functions which range from secondary metabolism to RNA modification. To date, nearly 35 compounds with the common 7-deazapurine core structure have been described. This article will illustrate the structural diversity of these compounds and review the current state of knowledge on the biosynthetic pathways that give rise to them.
Topics: Enzymes; Guanosine; Nucleoside Q; Purines; Pyrimidines; Pyrroles; RNA, Transfer
PubMed: 22382038
DOI: 10.1016/j.bioorg.2012.01.001 -
Cancer Science Jul 2013This review focuses primarily on my own research, including pathogenic mechanisms of microbial infection, vascular permeability in infection and tumors, and effects of... (Review)
Review
This review focuses primarily on my own research, including pathogenic mechanisms of microbial infection, vascular permeability in infection and tumors, and effects of nitric oxide (NO), superoxide anion radical (O₂⁻), and 8-nitroguanosine in the enhanced permeability and retention (EPR) effect for the tumor-selective delivery of macromolecular agents (nanomedicines). Infection-induced vascular permeability is mediated by activation of the kinin-generating protease cascade (kallikrein-kinin) triggered by exogenous microbial proteases. A similar mechanism operates in cancer tissues and in carcinomatosis of the pleural and peritoneal cavities. Infection also stimulates O₂⁻ generation via activation of xanthine oxidase while generating NO by inducing NO synthase. These chemicals function in mutation and carcinogenesis and promote inflammation, in which peroxynitrite (a product of O₂⁻ and NO) activates MMP, damages DNA and RNA, and regenerates 8-nitroguanosine and 8-oxoguanosine. We showed vascular permeability by using macromolecular drugs, which are not simply extravasated through the vascular wall into the tumor interstitium but remain there for prolonged periods. We thus discovered the EPR effect, which led to the rational development of tumor-selective delivery of polymer conjugates, micellar and liposomal drugs, and genes. Our styrene-maleic acid copolymer conjugated with neocarzinostatin was the first agent of its kind used to treat hepatoma. The EPR effect occurs not only because of defective vascular architecture but also through the generation of various vascular mediators such as kinin, NO, and vascular endothelial growth factor. Although most solid tumors, including human tumors, show the EPR effect, heterogeneity of tumor tissue may impede drug delivery. This review describes the barriers and countermeasures for improved drug delivery to tumors by using nanomedicines.
Topics: Animals; Antineoplastic Agents; Capillary Permeability; Free Radicals; Guanosine; Humans; Infections; Nanomedicine; Neoplasms; Nitric Oxide; Nitro Compounds
PubMed: 23495730
DOI: 10.1111/cas.12152 -
Oxidative Medicine and Cellular... 2014Aging is a complex process of organism decline in physiological functions. There is no clear theory explaining this phenomenon, but the most accepted one is the... (Review)
Review
Aging is a complex process of organism decline in physiological functions. There is no clear theory explaining this phenomenon, but the most accepted one is the oxidative stress theory of aging. Biomarkers of oxidative stress, substances, which are formed during oxidative damage of phospholipids, proteins, and nucleic acids, are present in body fluids of diseased people as well as the healthy ones (in a physiological concentration). 8-iso prostaglandin F2α is the most prominent biomarker of phospholipid oxidative damage, o-tyrosine, 3-chlorotyrosine, and 3-nitrotyrosine are biomarkers of protein oxidative damage, and 8-hydroxy-2(')-deoxyguanosine and 8-hydroxyguanosine are biomarkers of oxidative damage of nucleic acids. It is thought that the concentration of biomarkers increases as the age of people increases. However, the concentration of biomarkers in body fluids is very low and, therefore, it is necessary to use a sensitive analytical method. A combination of HPLC and MS was chosen to determine biomarker concentration in three groups of healthy people of a different age (twenty, forty, and sixty years) in order to find a difference among the groups.
Topics: Aging; Biomarkers; DNA Damage; Dinoprost; Guanosine; Humans; Oxidative Stress; Proteins; Tyrosine
PubMed: 25147595
DOI: 10.1155/2014/562860