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      Post-translational modification of RNA m 6A demethylase ALKBH5 regulates ROS-induced DNA damage response

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          Abstract

          Faithful genome integrity maintenance plays an essential role in cell survival. Here, we identify the RNA demethylase ALKBH5 as a key regulator that protects cells from DNA damage and apoptosis during reactive oxygen species (ROS)-induced stress. We find that ROS significantly induces global mRNA N 6-methyladenosine (m 6A) levels by modulating ALKBH5 post-translational modifications (PTMs), leading to the rapid and efficient induction of thousands of genes involved in a variety of biological processes including DNA damage repair. Mechanistically, ROS promotes ALKBH5 SUMOylation through activating ERK/JNK signaling, leading to inhibition of ALKBH5 m 6A demethylase activity by blocking substrate accessibility. Moreover, ERK/JNK/ALKBH5-PTMs/m 6A axis is activated by ROS in hematopoietic stem/progenitor cells (HSPCs) in vivo in mice, suggesting a physiological role of this molecular pathway in the maintenance of genome stability in HSPCs. Together, our study uncovers a molecular mechanism involving ALKBH5 PTMs and increased mRNA m 6A levels that protect genomic integrity of cells in response to ROS.

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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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              N6-Methyladenosine in Nuclear RNA is a Major Substrate of the Obesity-Associated FTO

              Guifang Jia, Ye Fu, Xu Zhao … (2011)
              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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                Author and article information

                Contributors
                Fang Yu
                Jiangbo Wei:
                ORCID: https://orcid.org/0000-0003-2691-6490
                Xiaolong Cui
                Chunjie Yu
                Wei Ni
                Jörg Bungert:
                ORCID: https://orcid.org/0000-0003-1801-9706
                Lizi Wu:
                ORCID: https://orcid.org/0000-0002-0076-2617
                Chuan He
                Zhijian Qian:
                ORCID: https://orcid.org/0000-0001-5565-7534
                Journal
                Journal ID (nlm-ta): Nucleic Acids Res
                Journal ID (iso-abbrev): Nucleic Acids Res
                Journal ID (publisher-id): nar
                Title: Nucleic Acids Research
                Publisher: Oxford University Press
                ISSN (Print): 0305-1048
                ISSN (Electronic): 1362-4962
                Publication date Collection: 04 June 2021
                Publication date (Electronic): 28 May 2021
                Publication date PMC-release: 28 May 2021
                Volume: 49
                Issue: 10
                Pages: 5779-5797
                Affiliations
                Department of Medicine, UF Health Cancer Center, University of Florida , Gainesville, FL 32610, USA
                Department of Biochemistry and Molecular Biology, University of Florida , Gainesville, FL 32610, USA
                Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago , 929 East 57th Street, Chicago, IL 60637, USA
                Howard Hughes Medical Institute, The University of Chicago , 929 East 57th Street, Chicago, IL 60637, USA
                Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago , 929 East 57th Street, Chicago, IL 60637, USA
                Howard Hughes Medical Institute, The University of Chicago , 929 East 57th Street, Chicago, IL 60637, USA
                Department of Medicine, UF Health Cancer Center, University of Florida , Gainesville, FL 32610, USA
                Department of Molecular Genetics and Microbiology, UF Genetic Institute, University of Florida , FL 32610, USA
                Department of Biochemistry and Molecular Biology, University of Florida , Gainesville, FL 32610, USA
                Department of Molecular Genetics and Microbiology, UF Genetic Institute, University of Florida , FL 32610, USA
                Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago , 929 East 57th Street, Chicago, IL 60637, USA
                Howard Hughes Medical Institute, The University of Chicago , 929 East 57th Street, Chicago, IL 60637, USA
                Department of Medicine, UF Health Cancer Center, University of Florida , Gainesville, FL 32610, USA
                Department of Biochemistry and Molecular Biology, University of Florida , Gainesville, FL 32610, USA
                Author notes
                To whom correspondence should be addressed. Tel: +1 352 294 8984; Email: z.qian@ 123456ufl.edu
                Correspondence may also be addressed to Chuan He. Email: chuanhe@ 123456uchicago.edu

                The authors wish it to be known that, in their opinion, the first three authors should be regarded as Joint First Authors.

                Author information
                https://orcid.org/0000-0003-2691-6490
                https://orcid.org/0000-0003-1801-9706
                https://orcid.org/0000-0002-0076-2617
                https://orcid.org/0000-0001-5565-7534
                Article
                Publisher ID: gkab415
                DOI: 10.1093/nar/gkab415
                PMC ID: 8191756
                PubMed ID: 34048572
                SO-VID: e3806571-f41f-48bf-9085-1a67f9d457ab
                Copyright © © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date accepted : 30 April 2021
                Date revision received : 28 April 2021
                Date received : 22 February 2021
                Page count
                Pages: 19
                Funding
                Funded by: Leukemia and Lymphoma Society, DOI 10.13039/100005189;
                Funded by: Howard Hughes Medical Institute, DOI 10.13039/100000011;
                Funded by: UF startup;
                Award ID: 29050600-171-2200-ASHANDS-2701NCIZQ-45614298
                Categories
                Subject: AcademicSubjects/SCI00010
                Subject: Molecular Biology

                ScienceOpen disciplines: Genetics
                Data availability:
                ScienceOpen disciplines: Genetics

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