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PMID: 27558897 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex.

Nature communications ·Vol. 7 ·2016-00-25 ·Pages 12626

Du H, Zhao Y, He J, Zhang Y, Xi H, Liu M, Ma J, Wu L

Abstract

Methylation at the N6 position of adenosine (m(6)A) 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 m(6)A, the binding of which results in the alteration of the translation efficiency and stability of m(6)A-containing RNAs. However, the mechanism by which YTHDF proteins cause the degradation of m(6)A-containing RNAs is poorly understood. Here we report that m(6)A-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 m(6)A-containing RNAs by CAF1 and CCR4. Therefore, we have uncovered the mechanism of YTHDF2-mediated degradation of m(6)A-containing RNAs in mammalian cells.

MeSH Terms
Adenosine/genetics,metabolism HEK293 Cells HeLa Cells Humans Methylation Polyadenylation Protein Binding/genetics Protein Domains/genetics RNA Stability RNA, Messenger/metabolism RNA-Binding Proteins/genetics,isolation & purification,metabolism Receptors, CCR4/genetics,metabolism Recombinant Proteins/genetics,isolation & purification,metabolism Ribonucleases/genetics,metabolism Transcription Factors/genetics,metabolism
Chemicals
CCR4 protein, human CNOT1 protein, human CNOT8 protein, human RNA, Messenger RNA-Binding Proteins Receptors, CCR4 Recombinant Proteins Transcription Factors YTHDF2 protein, human Ribonucleases mRNA deadenylase Adenosine
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Du Hao
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, 320 Yue Yang Road, Shanghai 200031, China. | CAS-Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China. | 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, Shanghai 200031, China.
Zhao Ya
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, 320 Yue Yang Road, Shanghai 200031, China. | CAS-Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China. | 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, Shanghai 200031, China.
He Jinqiu
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Department of Biochemistry, Institute of Plant Biology, School of Life Sciences, Fudan University, Shanghai 200433, China.
Zhang Yao
Shanghai Institute of Planned Parenthood Research, Shanghai 200032, China.
Xi Hairui
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, 320 Yue Yang Road, Shanghai 200031, China. | CAS-Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China. | 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, Shanghai 200031, China. | School of Life Sciences, Shanghai University, 333 Nanchen Road, Shanghai 200444, China.
Liu Mofang
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, Shanghai 200031, China.
Ma Jinbiao
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Department of Biochemistry, Institute of Plant Biology, School of Life Sciences, Fudan University, Shanghai 200433, China.
Wu Ligang
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, 320 Yue Yang Road, Shanghai 200031, China. | CAS-Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China. | 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, Shanghai 200031, China.
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Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/ncomms12626
Published
2016-00-25
Epub
2016-00-25
Pages
12626
Language
English
Region
England
NLM ID
101528555
PMCID
PMC5007331
Subset
IM
External Links
PubMed source DOI: 10.1038/ncomms12626 PMC Full Text View journal details
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