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YTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4–NOT deadenylase complex

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  • Hao Du

    (State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences
    CAS-Shanghai Science Research Center, Chinese Academy of Sciences
    Shanghai Key Laboratory of Molecular Andrology, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences)

  • Ya Zhao

    (State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences
    CAS-Shanghai Science Research Center, Chinese Academy of Sciences
    Shanghai Key Laboratory of Molecular Andrology, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences)

  • Jinqiu He

    (State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Institute of Plant Biology, School of Life Sciences, Fudan University)

  • Yao Zhang

    (Shanghai Institute of Planned Parenthood Research)

  • Hairui Xi

    (State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences
    CAS-Shanghai Science Research Center, Chinese Academy of Sciences
    Shanghai Key Laboratory of Molecular Andrology, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    School of Life Sciences, Shanghai University)

  • Mofang Liu

    (Shanghai Key Laboratory of Molecular Andrology, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences)

  • Jinbiao Ma

    (State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Institute of Plant Biology, School of Life Sciences, Fudan University)

  • Ligang Wu

    (State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences
    CAS-Shanghai Science Research Center, Chinese Academy of Sciences
    Shanghai Key Laboratory of Molecular Andrology, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences)

Abstract

Methylation at the N6 position of adenosine (m6A) is the most abundant RNA modification within protein-coding and long noncoding RNAs in eukaryotes and is a reversible process with important biological functions. YT521-B homology domain family (YTHDF) proteins are the readers of m6A, the binding of which results in the alteration of the translation efficiency and stability of m6A-containing RNAs. However, the mechanism by which YTHDF proteins cause the degradation of m6A-containing RNAs is poorly understood. Here we report that m6A-containing RNAs exhibit accelerated deadenylation that is mediated by the CCR4–NOT deadenylase complex. We further show that YTHDF2 recruits the CCR4–NOT complex through a direct interaction between the YTHDF2 N-terminal region and the SH domain of the CNOT1 subunit, and that this recruitment is essential for the deadenylation of m6A-containing RNAs by CAF1 and CCR4. Therefore, we have uncovered the mechanism of YTHDF2-mediated degradation of m6A-containing RNAs in mammalian cells.

Suggested Citation

  • Hao Du & Ya Zhao & Jinqiu He & Yao Zhang & Hairui Xi & Mofang Liu & Jinbiao Ma & Ligang Wu, 2016. "YTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4–NOT deadenylase complex," Nature Communications, Nature, vol. 7(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12626
    DOI: 10.1038/ncomms12626
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    1. Christopher J. Gilbert & Charles P. Rabolli & Volha A. Golubeva & Kristina M. Sattler & Meifang Wang & Arsh Ketabforoush & W. David Arnold & Christoph Lepper & Federica Accornero, 2024. "YTHDF2 governs muscle size through a targeted modulation of proteostasis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Debjit Khan & Iyappan Ramachandiran & Kommireddy Vasu & Arnab China & Krishnendu Khan & Fabio Cumbo & Dalia Halawani & Fulvia Terenzi & Isaac Zin & Briana Long & Gregory Costain & Susan Blaser & Amand, 2024. "Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m6A site accessibility," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    3. Shujie Chen, & Lu Zhang & Mengjie Li & Ying Zhang & Meng Sun & Lingfang Wang & Jiebo Lin & Yun Cui & Qian Chen & Chenqi Jin & Xiang Li & Boya Wang & Hao Chen & Tianhua Zhou & Liangjing Wang & Chih-Hun, 2022. "Fusobacterium nucleatum reduces METTL3-mediated m6A modification and contributes to colorectal cancer metastasis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    4. Xiang Zhang & Huilong Yin & Xiaofang Zhang & Xunliang Jiang & Yongkang Liu & Haolin Zhang & Yingran Peng & Da Li & Yanping Yu & Jinbao Zhang & Shuli Cheng & Angang Yang & Rui Zhang, 2022. "N6-methyladenosine modification governs liver glycogenesis by stabilizing the glycogen synthase 2 mRNA," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    5. Xiaojie Ma & Jie Cao & Ziyu Zhou & Yunkun Lu & Qin Li & Yan Jin & Guo Chen & Weiyun Wang & Wenyan Ge & Xi Chen & Zhensheng Hu & Xiao Shu & Qian Deng & Jiaqi Pu & Chengzhen Liang & Junfen Fu & Jianzhao, 2022. "N6-methyladenosine modification-mediated mRNA metabolism is essential for human pancreatic lineage specification and islet organogenesis," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    6. Maryam Ghashghaei & Yilin Liu & James Ettles & Giuseppe Bombaci & Niveditha Ramkumar & Zongmin Liu & Leo Escano & Sandra Spencer Miko & Yerin Kim & Joseph A. Waldron & Kim Do & Kyle MacPherson & Katie, 2024. "Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    7. Kriti Shah & Shiyang He & David J. Turner & Joshua Corbo & Khadija Rebbani & Daniel Dominguez & Joseph M. Bateman & Sihem Cheloufi & Cátia Igreja & Eugene Valkov & Jernej Murn, 2024. "Regulation by the RNA-binding protein Unkempt at its effector interface," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    8. Kristin A. Fluke & Ryan T. Fuchs & Yueh-Lin Tsai & Victoria Talbott & Liam Elkins & Hallie P. Febvre & Nan Dai & Eric J. Wolf & Brett W. Burkhart & Jackson Schiltz & G. Brett Robb & Ivan R. Corrêa & T, 2024. "The extensive m5C epitranscriptome of Thermococcus kodakarensis is generated by a suite of RNA methyltransferases that support thermophily," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    9. Fabian Poetz & Joshua Corbo & Yevgen Levdansky & Alexander Spiegelhalter & Doris Lindner & Vera Magg & Svetlana Lebedeva & Jörg Schweiggert & Johanna Schott & Eugene Valkov & Georg Stoecklin, 2021. "RNF219 attenuates global mRNA decay through inhibition of CCR4-NOT complex-mediated deadenylation," Nature Communications, Nature, vol. 12(1), pages 1-19, December.

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