m6A-dependent regulation of messenger RNA stability

By Xiao Wang, Zhike Lu, Adrian Gomez, Gary Chung Hon, Y. Yue, Dali Han, Ye Fu, Marc-André Parisien, Qing Dai, G. Jia and 3 more. Nature, 2013

3,208 citations recorded by the source corpus.

N6-methyladenosine (m6A) is the most prevalent internal (non-cap) modification present in the messenger RNA of all higher eukaryotes. Although essential to cell viability and development, 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. Here we show that m6A is selectively recognized by the human YTH domain family 2 (YTHDF2) ‘reader’ 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. The carboxy-terminal domain of YTHDF2 selectively binds to m6A-containing mRNA, whereas the amino-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 selectively binding proteins to affect the translation status and lifetime of mRNA.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/ac6d85d26e701a456a8a0ef82f3508ea016da2b2

How researchers see this paper

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In Molecular Biology

1. Chuan He
2. Samie R. Jaffrey
3. Kate D. Meyer
4. Hailing Shi
5. K. Doxtader
6. Ping-yuan Wang
7. Y. Nam
8. Syuzo Kaneko

Citations in the corpus

• Transcriptome-wide mapping reveals widespread dynamic regulated pseudouridylation of ncRNA and mRNA (2014, neutral): “Alternatively, J could target specific mRNAs to heat-shock-induced stress granules in a similar manner to m6A destabilization of RNA by directing it to P bodies (Wang et al., 2014).”
• A majority of m6A residues are in the last exons, allowing the potential for 3′ UTR regulation (2015, methodology): “With the commercial availability of m6A-specific antibodies and RNA-seq, thousands of m6A residues in human and yeast polyA+ RNA have been reported (Dominissini et al. 2012; Meyer et al. 2012; Fustin et al. 2013; Schwartz et al. 2013, 2014; Wang et al. 2014).”
• RNA modifications modulate gene expression during development (2018, positive): “For example, YTHDF2 binds to m 6 A in mRNA and targets the transcripts for degradation ( 3, 8 ), and YTHDF1, YTHDF3 and eIF3a promote translation of m 6 A containing transcripts ( 3, 9, 10 ).”
• Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases (2016, positive): “In vitro studies showed that Mettl3 and Mettl14 help each other’s protein stability, and that they synergize to produce m6A marks on cognate RNA oligonucleotides (Liu et al., 2014; Wang et al., 2014b).”
• Critical Roles of N6-Methyladenosine (m6A) in Cancer and Virus Infection (2020, methodology): “Biochemical purification following mass spectrometric (MS)-analysis revealed that the YTH domain family 1 (YTHDF1), 2 (YTHDF2), and 3 (YTHDF3) are primary members of m6A reader proteins, which devote to recognizing bases that undergo m6A methylation, participating in downstream translation, mRNA deg”