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      Detailed resume of RNA m 6A demethylases

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          Abstract

          N6-Methyladenosine (m 6A) is the most abundant internal modification in eukaryotic mRNA, playing critical role in various bioprocesses. Like other epigenetic modifications, m 6A modification can be catalyzed by the methyltransferase complex and erased dynamically to maintain cells homeostasis. Up to now, only two m 6A demethylases have been reported, fat mass and obesity-associated protein (FTO) and alkylation protein AlkB homolog 5 (ALKBH5), involving in a wide range of mRNA biological progress, including mRNA shearing, export, metabolism and stability. Furthermore, they participate in many significantly biological signaling pathway, and contribute to the progress and development of cancer along with other diseases. In this review, we focus on the studies about structure, inhibitors development and biological function of FTO and ALKBH5.

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          This review systematically describes the chemical and biological functions of RNA demethylases FTO and ALKBH5, from their crystal structure to inhibitors development and screening, demethylation mechanism and substrates to biological functions and roles in diseases.

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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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            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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              N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency.

              Xiao Wang, Boxuan Simen Zhao, Ian A Roundtree … (2015)
              N(6)-methyladenosine (m(6)A) is the most abundant internal modification in mammalian mRNA. This modification is reversible and non-stoichiometric and adds another layer to the dynamic control of mRNA metabolism. The stability of m(6)A-modified mRNA is regulated by an m(6)A reader protein, human YTHDF2, which recognizes m(6)A and reduces the stability of target transcripts. Looking at additional functional roles for the modification, we find that another m(6)A reader protein, human YTHDF1, actively promotes protein synthesis by interacting with translation machinery. In a unified mechanism of m(6)A-based regulation in the cytoplasm, YTHDF2-mediated degradation controls the lifetime of target transcripts, whereas YTHDF1-mediated translation promotion increases translation efficiency, ensuring effective protein production from dynamic transcripts that are marked by m(6)A. Therefore, the m(6)A modification in mRNA endows gene expression with fast responses and controllable protein production through these mechanisms.
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                Author and article information

                Contributors
                Yi-Chao Zheng
                Hong-Min Liu
                Journal
                Journal ID (nlm-ta): Acta Pharm Sin B
                Journal ID (iso-abbrev): Acta Pharm Sin B
                Title: Acta Pharmaceutica Sinica. B
                Publisher: Elsevier
                ISSN (Print): 2211-3835
                ISSN (Electronic): 2211-3843
                Publication date PMC-release: 11 January 2022
                Publication date (Print): May 2022
                Publication date (Electronic): 11 January 2022
                Volume: 12
                Issue: 5
                Pages: 2193-2205
                Affiliations
                [a ]Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450052, China
                [b ]Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China
                [c ]State Key Laboratory of Esophageal Cancer Prevention & Treatment, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, China
                [d ]Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
                [e ]The School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
                Author notes
                [∗ ]Corresponding authors. Tel./fax: +86 371 67781739. yichaozheng@ 123456zzu.edu.cn liuhm@ 123456zzu.edu.cn
                [†]

                These authors made equal contributions to this work.

                Article
                Publisher Item ID: S2211-3835(22)00016-8
                DOI: 10.1016/j.apsb.2022.01.003
                PMC ID: 9136571
                PubMed ID: 35646549
                SO-VID: d97d277f-3ca6-4482-96d4-b6169554c1b3
                Copyright © © 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 18 September 2021
                Date revision received : 26 November 2021
                Date accepted : 3 January 2022
                Categories
                Subject: Review

                Keywords: fto,alkbh5,rna demethylation,diseases,inhibitors,screening
                Data availability:
                Keywords: fto, alkbh5, rna demethylation, diseases, inhibitors, screening

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