Three distinct 3-methylcytidine (m3C) methyltransferases modify tRNA and mRNA in mice and humans
Chemical RNA modifications are central features of epitranscriptomics, highlighted by the discovery of modified ribonucleosides in mRNA and exemplified by the critical roles of RNA modifications in normal physiology and disease. Despite a resurgent interest in these modifications, the biochemistry o...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2018
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| Online Access: | https://hdl.handle.net/10356/87240 http://hdl.handle.net/10220/44345 |
| _version_ | 1824454208686915584 |
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| author | Xu, Luang Liu, Xinyu Sheng, Na Oo, Kyaw Soe Liang, Junxin Chionh, Yok Hian Xu, Juan Ye, Fuzhou Gao, Yong-Gui Dedon, Peter C. Fu, Xin-Yuan |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Xu, Luang Liu, Xinyu Sheng, Na Oo, Kyaw Soe Liang, Junxin Chionh, Yok Hian Xu, Juan Ye, Fuzhou Gao, Yong-Gui Dedon, Peter C. Fu, Xin-Yuan |
| author_sort | Xu, Luang |
| collection | NTU |
| description | Chemical RNA modifications are central features of epitranscriptomics, highlighted by the discovery of modified ribonucleosides in mRNA and exemplified by the critical roles of RNA modifications in normal physiology and disease. Despite a resurgent interest in these modifications, the biochemistry of 3-methylcytidine (m3C) formation in mammalian RNAs is still poorly understood. However, the recent discovery of trm141 as the second gene responsible for m3C presence in RNA in fission yeast raises the possibility that multiple enzymes are involved in m3C formation in mammals as well. Here, we report the discovery and characterization of three distinct m3C-contributing enzymes in mice and humans. We found that methyltransferase-like (METTL) 2 and 6 contribute m3C in specific tRNAs and that METTL8 only contributes m3C to mRNA. MS analysis revealed that there is an ∼30–40% and ∼10–15% reduction, respectively, in METTL2 and -6 null-mutant cells, of m3C in total tRNA, and primer extension analysis located METTL2-modified m3C at position 32 of tRNAThr isoacceptors and tRNAArg(CCU). We also noted that METTL6 interacts with seryl-tRNA synthetase in an RNA-dependent manner, suggesting a role for METTL6 in modifying serine tRNA isoacceptors. METTL8, however, modified only mRNA, as determined by biochemical and genetic analyses in Mettl8 null-mutant mice and two human METTL8 mutant cell lines. Our findings provide the first evidence of the existence of m3C modification in mRNA, and the discovery of METTL8 as an mRNA m3C writer enzyme opens the door to future studies of other m3C epitranscriptomic reader and eraser functions. |
| first_indexed | 2025-02-19T03:18:40Z |
| format | Journal Article |
| id | ntu-10356/87240 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2025-02-19T03:18:40Z |
| publishDate | 2018 |
| record_format | dspace |
| spelling | ntu-10356/872402023-02-28T17:00:36Z Three distinct 3-methylcytidine (m3C) methyltransferases modify tRNA and mRNA in mice and humans Xu, Luang Liu, Xinyu Sheng, Na Oo, Kyaw Soe Liang, Junxin Chionh, Yok Hian Xu, Juan Ye, Fuzhou Gao, Yong-Gui Dedon, Peter C. Fu, Xin-Yuan School of Biological Sciences Human Mouse Chemical RNA modifications are central features of epitranscriptomics, highlighted by the discovery of modified ribonucleosides in mRNA and exemplified by the critical roles of RNA modifications in normal physiology and disease. Despite a resurgent interest in these modifications, the biochemistry of 3-methylcytidine (m3C) formation in mammalian RNAs is still poorly understood. However, the recent discovery of trm141 as the second gene responsible for m3C presence in RNA in fission yeast raises the possibility that multiple enzymes are involved in m3C formation in mammals as well. Here, we report the discovery and characterization of three distinct m3C-contributing enzymes in mice and humans. We found that methyltransferase-like (METTL) 2 and 6 contribute m3C in specific tRNAs and that METTL8 only contributes m3C to mRNA. MS analysis revealed that there is an ∼30–40% and ∼10–15% reduction, respectively, in METTL2 and -6 null-mutant cells, of m3C in total tRNA, and primer extension analysis located METTL2-modified m3C at position 32 of tRNAThr isoacceptors and tRNAArg(CCU). We also noted that METTL6 interacts with seryl-tRNA synthetase in an RNA-dependent manner, suggesting a role for METTL6 in modifying serine tRNA isoacceptors. METTL8, however, modified only mRNA, as determined by biochemical and genetic analyses in Mettl8 null-mutant mice and two human METTL8 mutant cell lines. Our findings provide the first evidence of the existence of m3C modification in mRNA, and the discovery of METTL8 as an mRNA m3C writer enzyme opens the door to future studies of other m3C epitranscriptomic reader and eraser functions. NRF (Natl Research Foundation, S’pore) MOE (Min. of Education, S’pore) Published version 2018-01-26T01:42:56Z 2019-12-06T16:37:56Z 2018-01-26T01:42:56Z 2019-12-06T16:37:56Z 2017 Journal Article Xu, L., Liu, X., Sheng, N., Oo, K. S., Liang, J., Chionh, Y. H., et al. (2017). Three distinct 3-methylcytidine (m3C) methyltransferases modify tRNA and mRNA in mice and humans. Journal of Biological Chemistry, 292(35), 14695-14703. 0021-9258 https://hdl.handle.net/10356/87240 http://hdl.handle.net/10220/44345 10.1074/jbc.M117.798298 en Journal of Biological Chemistry © 2017 American Society for Biochemistry and Molecular Biology (ASBMB). This paper was published in Journal of Biological Chemistry and is made available as an electronic reprint (preprint) with permission of American Society for Biochemistry and Molecular Biology (ASBMB). The published version is available at: [http://dx.doi.org/10.1074/jbc.M117.798298]. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law. 10 p. application/pdf |
| spellingShingle | Human Mouse Xu, Luang Liu, Xinyu Sheng, Na Oo, Kyaw Soe Liang, Junxin Chionh, Yok Hian Xu, Juan Ye, Fuzhou Gao, Yong-Gui Dedon, Peter C. Fu, Xin-Yuan Three distinct 3-methylcytidine (m3C) methyltransferases modify tRNA and mRNA in mice and humans |
| title | Three distinct 3-methylcytidine (m3C) methyltransferases modify tRNA and mRNA in mice and humans |
| title_full | Three distinct 3-methylcytidine (m3C) methyltransferases modify tRNA and mRNA in mice and humans |
| title_fullStr | Three distinct 3-methylcytidine (m3C) methyltransferases modify tRNA and mRNA in mice and humans |
| title_full_unstemmed | Three distinct 3-methylcytidine (m3C) methyltransferases modify tRNA and mRNA in mice and humans |
| title_short | Three distinct 3-methylcytidine (m3C) methyltransferases modify tRNA and mRNA in mice and humans |
| title_sort | three distinct 3 methylcytidine m3c methyltransferases modify trna and mrna in mice and humans |
| topic | Human Mouse |
| url | https://hdl.handle.net/10356/87240 http://hdl.handle.net/10220/44345 |
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