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      Biological roles of RNA m 5C modification and its implications in Cancer immunotherapy

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          Abstract

          Epigenetics including DNA and RNA modifications have always been the hotspot field of life sciences in the post-genome era. Since the first mapping of N6-methyladenosine (m 6A) and the discovery of its widespread presence in mRNA, there are at least 160-170 RNA modifications have been discovered. These methylations occur in different RNA types, and their distribution is species-specific. 5-methylcytosine (m 5C) has been found in mRNA, rRNA and tRNA of representative organisms from all kinds of species. As reversible epigenetic modifications, m 5C modifications of RNA affect the fate of the modified RNA molecules and play important roles in various biological processes including RNA stability control, protein synthesis, and transcriptional regulation. Furthermore, accumulative evidence also implicates the role of RNA m 5C in tumorigenesis. Here, we review the latest progresses in the biological roles of m 5C modifications and how it is regulated by corresponding “writers”, “readers” and “erasers” proteins, as well as the potential molecular mechanism in tumorigenesis and cancer immunotherapy.

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          Most cited references122

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          m6A-dependent regulation of messenger RNA stability

          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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            Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA.

            DNA and RNA stimulate the mammalian innate immune system through activation of Toll-like receptors (TLRs). DNA containing methylated CpG motifs, however, is not stimulatory. Selected nucleosides in naturally occurring RNA are also methylated or otherwise modified, but the immunomodulatory effects of these alterations remain untested. We show that RNA signals through human TLR3, TLR7, and TLR8, but incorporation of modified nucleosides m5C, m6A, m5U, s2U, or pseudouridine ablates activity. Dendritic cells (DCs) exposed to such modified RNA express significantly less cytokines and activation markers than those treated with unmodified RNA. DCs and TLR-expressing cells are potently activated by bacterial and mitochondrial RNA, but not by mammalian total RNA, which is abundant in modified nucleosides. We conclude that nucleoside modifications suppress the potential of RNA to activate DCs. The innate immune system may therefore detect RNA lacking nucleoside modification as a means of selectively responding to bacteria or necrotic tissue.
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              RNA modifications modulate gene expression during development

              RNA modifications have recently emerged as critical posttranscriptional regulators of gene expression programs. They affect diverse eukaryotic biological processes, and the correct deposition of many of these modifications is required for normal development. Messenger RNA (mRNA) modifications regulate various aspects of mRNA metabolism. For example, N 6 -methyladenosine (m 6 A) affects the translation and stability of the modified transcripts, thus providing a mechanism to coordinate the regulation of groups of transcripts during cell state maintenance and transition. Similarly, some modifications in transfer RNAs are essential for RNA structure and function. Others are deposited in response to external cues and adapt global protein synthesis and gene-specific translational accordingly and thereby facilitate proper development.
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                Author and article information

                Contributors
                jianyez@163.com
                yuxycn@aliyun.com
                mateng82913@163.com
                Journal
                Biomark Res
                Biomark Res
                Biomarker Research
                BioMed Central (London )
                2050-7771
                1 April 2022
                1 April 2022
                2022
                : 10
                : 15
                Affiliations
                [1 ]GRID grid.252251.3, ISNI 0000 0004 1757 8247, Department of Biochemistry and Molecular Biology, School of Integrated Chinese and Western Medicine, , Anhui University of Chinese Medicine, ; Hefei, 230012 China
                [2 ]Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, 230012 China
                [3 ]GRID grid.410737.6, ISNI 0000 0000 8653 1072, Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, , School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, ; Guangzhou, 511436 China
                [4 ]GRID grid.24696.3f, ISNI 0000 0004 0369 153X, Department of Cellular and Molecular Biology, Beijing Chest Hospital, , Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, ; Beijing, 101149 China
                [5 ]GRID grid.5330.5, ISNI 0000 0001 2107 3311, Division of Surgical Research, Department of Surgery, , University Medical Center Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, ; 91054 Erlangen, Germany
                [6 ]GRID grid.5330.5, ISNI 0000 0001 2107 3311, Division of Molecular and Experimental Surgery, Department of Surgery, , University Medical Center Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, ; 91054 Erlangen, Germany
                Author information
                http://orcid.org/0000-0002-8360-1543
                Article
                362
                10.1186/s40364-022-00362-8
                8973801
                35365216
                9846032b-6d76-481e-9ea1-38c10b55b72d
                © The Author(s) 2022

                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
                : 15 December 2021
                : 3 March 2022
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                Review
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                © The Author(s) 2022

                epigenetics,rna methylation modification,5-methylcytosine (m5c),non-coding rnas,cancer immunotherapy

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