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

By Hao Du, Ya Zhao, Jinqiu He, Yao Zhang, Hairui Xi, Mofang Liu, Jinbiao Ma, Ligang Wu. Nature Communications, 2016

1,313 citations recorded by the source corpus.

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. The YTHDF family of proteins are able to bind and regulate the stability of methylated N6 RNA. Here the authors show that this decreased m6A RNA stability is mediated by direct recruitment of the CCR4–NOT deadenylase complex through YTHDF proteins.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/4382f4e3e4a6a82842440cafe22ac3c67e79d48f

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In Cancer Research

1. Chuan He
2. Hailing Shi
3. I. A. Roundtree
4. Samie R. Jaffrey

In Molecular Biology

1. Chuan He
2. Samie R. Jaffrey
3. S. Zaccara
4. Hailing Shi
5. Jiangbo W
6. Syuzo Kaneko
7. Masaaki Komatsu
8. Ken Asada

Citations in the corpus

• YTH Domain: A Family of N6-methyladenosine (m6A) Readers (2018, background): “After being targeted to a specific site via m(6)A recognition, YTHDF2 recruits the CCR4-NOT deadenylase complex to destabilize and further decay target mRNAs (Figure 1) [37,39].”
• Zc3h13 regulates nuclear RNA m6A methylation and mouse embryonic stem cell self-renewal (2018, methodology): “…pPB-Flag/HA-Zc3h13-(1-1460) This paper N/A plasmid: pPB-Flag/HA-Zc3h13-(1461-1729) This paper N/A plasmid: pTBG Laboratory of Li-Gang Wu (Du et al., 2016) N/A pPB-BG-Atg13 This paper N/A pPB-BG-Atg13-mut This paper N/A Software and Algorithms Tophat2 (Trapnell et al., 2009)…”
• Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation (2017, neutral): “To further assess our model that mRNA decay regulates neuronal lineage gene expression in RGCs, we performed in vivo KD experiments for the components of the CCR4-NOT complex (Cnot7 and Cnot1), a major cytoplasmic mRNA deadenylase complex responsible for mRNA decay (Du et al., 2016; Schoenberg and M”
• A Unified Model for the Function of YTHDF Proteins in Regulating m6A-Modified mRNA (2020, background): “A recent study showed that all three DF proteins bind CNOT1 and elicit mRNA degradation (Du et al., 2016).”
• m6A RNA methylation: from mechanisms to therapeutic potential (2021, neutral): “YTHDF2 recruits the CCR4-NOT deadenylase complex to promote deadenylation and degradation of m 6 A-marked mRNAs and also recruits the RNase P/MRP complex to promote endoribonucleolytic cleavage of m 6 A-marked mRNAs (Du et al , 2016; Park et al , 2019).”
• YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs (2017, background): “Within the cytoplasm, YTHDF1 and YTHDF2 facilitate m6A-dependent translation initiation and m6A-dependent mRNA decay, respectively, under normal and stress conditions (Batista et al., 2014; Du et al., 2016; Geula et al., 2015; Liu et al., 2014; Wang et al., 2014a, 2014b, 2015; Zhou et al., 2015).”
• FMRP Modulates Neural Differentiation through m6A-Dependent mRNA Nuclear Export (2019, neutral): “…RNA on N 6 -adenosine (m 6 A) is emerging as a critical mechanism regulating different aspects of RNA metabolism and function, including stability (Du et al., 2016; Ke et al., 2017; Wang et al., 2014), localization (Roundtree et al., 2017), and translation (Lin et al., 2016; Meyer et al., 2015;…”
• Where, when and how: context-dependent functions of RNA methylation writers, readers, and erasers (2019, background): “Cytoplasmic YTHDF2 promotes degradation of its target transcripts partially through recruiting the CCR4-NOT deadenylase complex (Du et al., 2016; Wang et al., 2014).”
• Critical Roles of N6-Methyladenosine (m6A) in Cancer and Virus Infection (2020, background): “YTHDF2 is reported to destabilize the m6A containing mRNA, and YTHDF2 knockdown promotes the stability of target RNAs [26,62].”