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      The role of m 6A, m 5C and Ψ RNA modifications in cancer: Novel therapeutic opportunities

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          Abstract

          RNA modifications have recently emerged as critical posttranscriptional regulators of gene expression programmes. Significant advances have been made in understanding the functional role of RNA modifications in regulating coding and non-coding RNA processing and function, which in turn thoroughly shape distinct gene expression programmes. They affect diverse biological processes, and the correct deposition of many of these modifications is required for normal development. Alterations of their deposition are implicated in several diseases, including cancer. In this Review, we focus on the occurrence of N 6-methyladenosine (m 6A), 5-methylcytosine (m 5C) and pseudouridine (Ψ) in coding and non-coding RNAs and describe their physiopathological role in cancer. We will highlight the latest insights into the mechanisms of how these posttranscriptional modifications influence tumour development, maintenance, and progression. Finally, we will summarize the latest advances on the development of small molecule inhibitors that target specific writers or erasers to rewind the epitranscriptome of a cancer cell and their therapeutic potential.

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          Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq.

          Dan Dominissini, Sharon Moshitch-Moshkovitz, Schraga Schwartz … (2012)
          An extensive repertoire of modifications is known to underlie the versatile coding, structural and catalytic functions of RNA, but it remains largely uncharted territory. Although biochemical studies indicate that N(6)-methyladenosine (m(6)A) is the most prevalent internal modification in messenger RNA, an in-depth study of its distribution and functions has been impeded by a lack of robust analytical methods. Here we present the human and mouse m(6)A modification landscape in a transcriptome-wide manner, using a novel approach, m(6)A-seq, based on antibody-mediated capture and massively parallel sequencing. We identify over 12,000 m(6)A sites characterized by a typical consensus in the transcripts of more than 7,000 human genes. Sites preferentially appear in two distinct landmarks--around stop codons and within long internal exons--and are highly conserved between human and mouse. Although most sites are well preserved across normal and cancerous tissues and in response to various stimuli, a subset of stimulus-dependent, dynamically modulated sites is identified. Silencing the m(6)A methyltransferase significantly affects gene expression and alternative splicing patterns, resulting in modulation of the p53 (also known as TP53) signalling pathway and apoptosis. Our findings therefore suggest that RNA decoration by m(6)A has a fundamental role in regulation of gene expression.
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            m6A-dependent regulation of messenger RNA stability

            Xiao Wang, Zhike Lu, Adrián Gómez-Brandón … (2013)
            N6 -methyladenosine (m6A) is the most prevalent internal (non-cap) modification present in the messenger RNA (mRNA) of all higher eukaryotes 1,2 . Although essential to cell viability and development 3–5 , the exact role of m6A modification remains to be determined. The recent discovery of two m6A demethylases in mammalian cells highlighted the importance of m6A in basic biological functions and disease 6–8 . Here we show that m6A is selectively recognized by the human YTH domain family 2 (YTHDF2) protein to regulate mRNA degradation. We identified over 3,000 cellular RNA targets of YTHDF2, most of which are mRNAs, but which also include non-coding RNAs, with a conserved core motif of G(m6A)C. We further establish the role of YTHDF2 in RNA metabolism, showing that binding of YTHDF2 results in the localization of bound mRNA from the translatable pool to mRNA decay sites, such as processing bodies 9 . The C-terminal domain of YTHDF2 selectively binds to m6A-containing mRNA whereas the N-terminal domain is responsible for the localization of the YTHDF2-mRNA complex to cellular RNA decay sites. Our results indicate that the dynamic m6A modification is recognized by selective-binding proteins to affect the translation status and lifetime of mRNA.
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              Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons.

              Kate D Meyer, Yogesh Saletore, Paul Zumbo … (2012)
              Methylation of the N(6) position of adenosine (m(6)A) is a posttranscriptional modification of RNA with poorly understood prevalence and physiological relevance. The recent discovery that FTO, an obesity risk gene, encodes an m(6)A demethylase implicates m(6)A as an important regulator of physiological processes. Here, we present a method for transcriptome-wide m(6)A localization, which combines m(6)A-specific methylated RNA immunoprecipitation with next-generation sequencing (MeRIP-Seq). We use this method to identify mRNAs of 7,676 mammalian genes that contain m(6)A, indicating that m(6)A is a common base modification of mRNA. The m(6)A modification exhibits tissue-specific regulation and is markedly increased throughout brain development. We find that m(6)A sites are enriched near stop codons and in 3' UTRs, and we uncover an association between m(6)A residues and microRNA-binding sites within 3' UTRs. These findings provide a resource for identifying transcripts that are substrates for adenosine methylation and reveal insights into the epigenetic regulation of the mammalian transcriptome. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Sandra Blanco:
                ORCID: http://orcid.org/0000-0001-7352-9392
                sandra.blanco@usal.es
                Journal
                Journal ID (nlm-ta): Mol Cancer
                Journal ID (iso-abbrev): Mol Cancer
                Title: Molecular Cancer
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1476-4598
                Publication date (Electronic): 18 January 2021
                Publication date PMC-release: 18 January 2021
                Publication date Collection: 2021
                Volume: 20
                Electronic Location Identifier: 18
                Affiliations
                [1 ]GRID grid.11762.33, ISNI 0000 0001 2180 1817, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, , Consejo Superior de Investigaciones Científicas (CSIC) - University of Salamanca, ; 37007 Salamanca, Spain
                [2 ]GRID grid.411258.b, Instituto de Investigación Biomédica de Salamanca (IBSAL), , Hospital Universitario de Salamanca, ; 37007 Salamanca, Spain
                Author information
                http://orcid.org/0000-0001-7352-9392
                Article
                Publisher ID: 1263
                DOI: 10.1186/s12943-020-01263-w
                PMC ID: 7812662
                PubMed ID: 33461542
                SO-VID: 5347de92-3189-47d0-9d0a-ac57481428aa
                Copyright © © The Author(s) 2020
                License:

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                Date received : 20 June 2020
                Date accepted : 24 September 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100011033, Agencia Estatal de Investigación;
                Award ID: SAF2016-78667-R
                Award ID: PID2019-111692RB-I00
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100002704, Fundación Científica Asociación Española Contra el Cáncer;
                Award ID: LABAE19040BLAN
                Award Recipient :
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2021

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: cancer,inhibitors,anti-cancer therapy,proliferation,migration,epitranscriptome,rna modifications,n6-methyladenosine,m6a,5-methylcytosine,m5c,pseudouridine,ψ
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: cancer, inhibitors, anti-cancer therapy, proliferation, migration, epitranscriptome, rna modifications, n6-methyladenosine, m6a, 5-methylcytosine, m5c, pseudouridine, ψ

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