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      Minding the message: tactics controlling RNA decay, modification, and translation in virus-infected cells

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          Abstract

          In this review, Burgess et al. discuss strategies and mechanisms that control mRNA decay, modification, and translation in animal virus-infected cells. Besides settling infection outcomes, post-transcriptional gene regulation in virus-infected cells epitomizes fundamental physiological stress responses in health and disease.

          Abstract

          With their categorical requirement for host ribosomes to translate mRNA, viruses provide a wealth of genetically tractable models to investigate how gene expression is remodeled post-transcriptionally by infection-triggered biological stress. By co-opting and subverting cellular pathways that control mRNA decay, modification, and translation, the global landscape of post-transcriptional processes is swiftly reshaped by virus-encoded factors. Concurrent host cell-intrinsic countermeasures likewise conscript post-transcriptional strategies to mobilize critical innate immune defenses. Here we review strategies and mechanisms that control mRNA decay, modification, and translation in animal virus-infected cells. Besides settling infection outcomes, post-transcriptional gene regulation in virus-infected cells epitomizes fundamental physiological stress responses in health and disease.

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          A SARS-CoV-2 Protein Interaction Map Reveals Targets for Drug-Repurposing

          SUMMARY The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption 1,2 . There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
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            N6-Methyladenosine in Nuclear RNA is a Major Substrate of the Obesity-Associated FTO

            We report here that FTO (fat mass and obesity-associated protein) exhibits efficient oxidative demethylation activity of abundant N 6-methyladenosine (m6A) residues in RNA in vitro. FTO knockdown with siRNA led to an increased level of m6A in mRNA, whereas overexpression of FTO resulted in a decreased level of m6A in human cells. We further show that FTO partially colocalizes with nuclear speckles, supporting m6A in nuclear RNA as a physiological substrate of FTO.
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              ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility.

              N(6)-methyladenosine (m(6)A) is the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Here we report ALKBH5 as another mammalian demethylase that oxidatively reverses m(6)A in mRNA in vitro and in vivo. This demethylation activity of ALKBH5 significantly affects mRNA export and RNA metabolism as well as the assembly of mRNA processing factors in nuclear speckles. Alkbh5-deficient male mice have increased m(6)A in mRNA and are characterized by impaired fertility resulting from apoptosis that affects meiotic metaphase-stage spermatocytes. In accordance with this defect, we have identified in mouse testes 1,551 differentially expressed genes that cover broad functional categories and include spermatogenesis-related mRNAs involved in the p53 functional interaction network. The discovery of this RNA demethylase strongly suggests that the reversible m(6)A modification has fundamental and broad functions in mammalian cells. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Genes Dev
                Genes Dev
                genesdev
                GAD
                Genes & Development
                Cold Spring Harbor Laboratory Press
                0890-9369
                1549-5477
                1 February 2022
                : 36
                : 3-4
                : 108-132
                Affiliations
                [1 ]Department of Microbial Sciences, School of Biosciences and Medicine, University of Surrey, Guildford GU2 7XH, United Kingdom;
                [2 ]Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA;
                [3 ]Laura and Isaac Perlmutter Cancer Institute, New York University School of Medicine, New York, New York 10016, USA
                Author notes
                [4]

                These authors contributed equally to this work.

                Article
                8711660
                10.1101/gad.349276.121
                8887129
                35193946
                ebf4ff3d-85b3-4672-a520-856bd4d81ab2
                © 2022 Burgess et al.; Published by Cold Spring Harbor Laboratory Press

                This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

                History
                Page count
                Pages: 25
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases , doi 10.13039/100000060;
                Award ID: AI151436
                Award ID: AI166638
                Award ID: AI073898
                Award ID: AI152543
                Funded by: National Institute of General Medical Sciences , doi 10.13039/100000057;
                Award ID: GM056927
                Categories
                6
                13
                19
                Review

                rna decay,rna modification,animal viruses,infection stress,translational control

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