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Sequence- and structure-selective mRNA m5C methylation by NSUN6 in animals

Jianheng Liu, Tao Huang, Yusen Zhang, Tianxuan Zhao, Xueni Zhao, Wanying Chen, View ORCID ProfileRui Zhang
doi: https://doi.org/10.1101/2020.10.03.324707
Jianheng Liu
1MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, RNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, PR China
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Tao Huang
1MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, RNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, PR China
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  • For correspondence: zhangrui3@mail.sysu.edu.cn huangt93@mail.sysu.edu.cn
Yusen Zhang
1MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, RNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, PR China
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Tianxuan Zhao
1MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, RNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, PR China
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Xueni Zhao
1MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, RNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, PR China
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Wanying Chen
1MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, RNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, PR China
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Rui Zhang
1MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, RNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, PR China
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  • ORCID record for Rui Zhang
  • For correspondence: zhangrui3@mail.sysu.edu.cn huangt93@mail.sysu.edu.cn
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Abstract

mRNA m5C, which has recently been implicated in the regulation of mRNA mobility, metabolism, and translation, plays important regulatory roles in various biological events. Two types of m5C sites are found in mRNAs. Type I m5C sites, which contain a downstream G-rich triplet motif and are computationally predicted to locate in the 5’ end of putative hairpin structures, are methylated by NSUN2. Type II m5C sites contain a downstream UCCA motif and are computationally predicted to locate in the loops of putative hairpin structures. However, their biogenesis remains unknown. Here we identified NSUN6, a methyltransferase that is known to methylate C72 of tRNAThr and tRNACys, as an mRNA methyltransferase that targets Type II m5C sites. Combining the RNA secondary structure prediction, miCLIP, and results from a high-throughput mutagenesis analysis, we determined the RNA sequence and structural features governing the specificity of NSUN6-mediated mRNA methylation. Integrating these features into an NSUN6-RNA structural model, we identified an NSUN6 variant that largely loses tRNA methylation but retains mRNA methylation ability. Finally, we revealed a negative correlation between m5C methylation and translation efficiency. Our findings uncover that mRNA m5C is tightly controlled by an elaborate two-enzyme system, and the protein-RNA structure analysis strategy established may be applied to other RNA modification writers to distinguish the functions of different RNA substrates of a writer protein.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 04, 2020.
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Sequence- and structure-selective mRNA m5C methylation by NSUN6 in animals
Jianheng Liu, Tao Huang, Yusen Zhang, Tianxuan Zhao, Xueni Zhao, Wanying Chen, Rui Zhang
bioRxiv 2020.10.03.324707; doi: https://doi.org/10.1101/2020.10.03.324707
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Sequence- and structure-selective mRNA m5C methylation by NSUN6 in animals
Jianheng Liu, Tao Huang, Yusen Zhang, Tianxuan Zhao, Xueni Zhao, Wanying Chen, Rui Zhang
bioRxiv 2020.10.03.324707; doi: https://doi.org/10.1101/2020.10.03.324707

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