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      Viral modulation of cellular RNA alternative splicing: A new key player in virus–host interactions?

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          Abstract

          Upon viral infection, a tug of war is triggered between host cells and viruses to maintain/gain control of vital cellular functions, the result of which will ultimately dictate the fate of the host cell. Among these essential cellular functions, alternative splicing (AS) is an important RNA maturation step that allows exons, or parts of exons, and introns to be retained in mature transcripts, thereby expanding proteome diversity and function. AS is widespread in higher eukaryotes, as it is estimated that nearly all genes in humans are alternatively spliced. Recent evidence has shown that upon infection by numerous viruses, the AS landscape of host‐cells is affected. In this review, we summarize recent advances in our understanding of how virus infection impacts the AS of cellular transcripts. We also present various molecular mechanisms allowing viruses to modulate cellular AS. Finally, the functional consequences of these changes in the RNA splicing signatures during virus–host interactions are discussed.

          This article is categorized under:

          • RNA in Disease and Development > RNA in Disease

          • RNA Processing > Splicing Regulation/Alternative Splicing

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          Most cited references108

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          Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged.

          Alternative splicing of mRNA precursors is a nearly ubiquitous and extremely flexible point of gene control in humans. It provides cells with the opportunity to create protein isoforms of differing, even opposing, functions from a single gene. Cancer cells often take advantage of this flexibility to produce proteins that promote growth and survival. Many of the isoforms produced in this manner are developmentally regulated and are preferentially re-expressed in tumors. Emerging insights into this process indicate that pathways that are frequently deregulated in cancer often play important roles in promoting aberrant splicing, which in turn contributes to all aspects of tumor biology.
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            An amazing sequence arrangement at the 5' ends of adenovirus 2 messenger RNA.

            The 5' terminal sequences of several adenovirus 2 (Ad2) mRNAs, isolated late in infection, are complementary to sequences within the Ad2 genome which are remote from the DNA from which the main coding sequence of each mRNA is transcribed. This has been observed by forming RNA displacement loops (R loops) between Ad2 DNA and unfractionated polysomal RNA from infected cells. The 5' terminal sequences of mRNAs in R loops, variously located between positions 36 and 92, form complex secondary hybrids with single-stranded DNA from restriction endonuclease fragments containing sequences to the left of position 36 on the Ad2 genome. The structures visualized in the electron microscope show that short sequences coded at map positions 16.6, 19.6 and 26.6 on the R strand are joined to form a leader sequence of 150-200 nucleotides at the 5' end of many late mRNAs. A late mRNA which maps to the left of position 16.6 shows a different pattern of second site hybridization. It contains sequences from 4.9-6.0 linked directly to those from 9.6-10.9. These findings imply a new mechanism for the biosynthesis of Ad2 mRNA in mammalian cells.
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              Mechanism of alternative splicing and its regulation.

              Alternative splicing of precursor mRNA is an essential mechanism to increase the complexity of gene expression, and it plays an important role in cellular differentiation and organism development. Regulation of alternative splicing is a complicated process in which numerous interacting components are at work, including cis-acting elements and trans-acting factors, and is further guided by the functional coupling between transcription and splicing. Additional molecular features, such as chromatin structure, RNA structure and alternative transcription initiation or alternative transcription termination, collaborate with these basic components to generate the protein diversity due to alternative splicing. All these factors contributing to this one fundamental biological process add up to a mechanism that is critical to the proper functioning of cells. Any corruption of the process may lead to disruption of normal cellular function and the eventuality of disease. Cancer is one of those diseases, where alternative splicing may be the basis for the identification of novel diagnostic and prognostic biomarkers, as well as new strategies for therapy. Thus, an in-depth understanding of alternative splicing regulation has the potential not only to elucidate fundamental biological principles, but to provide solutions for various diseases.
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                Author and article information

                Contributors
                martin.bisaillon@usherbrooke.ca
                Journal
                Wiley Interdiscip Rev RNA
                Wiley Interdiscip Rev RNA
                10.1002/(ISSN)1757-7012
                WRNA
                Wiley Interdisciplinary Reviews. RNA
                John Wiley & Sons, Inc. (Hoboken, USA )
                1757-7004
                1757-7012
                29 April 2019
                Sep-Oct 2019
                : 10
                : 5 ( doiID: 10.1002/wrna.v10.5 )
                : e1543
                Affiliations
                [ 1 ] Département de biochimie, Faculté de médecine et des sciences de la santé Université de Sherbrooke Sherbrooke Québec Canada
                [ 2 ] Département de microbiologie, infectiologie et immunologie, Faculté de médecine Université de Montréal Montréal Québec Canada
                Author notes
                [*] [* ] Correspondence

                Martin Bisaillon, Département de biochimie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada J1E 4K8.

                Email: martin.bisaillon@ 123456usherbrooke.ca

                Author information
                https://orcid.org/0000-0001-7822-0933
                Article
                WRNA1543
                10.1002/wrna.1543
                6767064
                31034770
                48ec87fe-0573-4393-a35e-0ff0803004f7
                © 2019 The Authors. WIREs RNA published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 13 December 2018
                : 25 March 2019
                : 08 April 2019
                Page count
                Figures: 3, Tables: 4, Pages: 20, Words: 16098
                Funding
                Funded by: Natural Sciences and Engineering Research Council of Canada
                Award ID: RGPIN‐03736‐2017
                Award ID: RGPIN‐2016‐03916
                Funded by: Canadian Institutes of Health Research
                Categories
                RNA in Disease
                Splicing Regulation/Alternative Splicing
                Advanced Review
                Advanced Reviews
                Custom metadata
                2.0
                wrna1543
                September/October 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.9 mode:remove_FC converted:30.09.2019

                rna alternative splicing,virus,virus–host interactions

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