Reversible methylation of m6Am in the 5′ cap controls mRNA stability

By J. Mauer, Xiaobing Luo, Alexandre Blanjoie, Xinfu Jiao, Anya V. Grozhik, D. P. Patil, Bastian Linder, Brian F. Pickering, J. Vasseur, Qiuying Chen and 5 more. Nature, 2016

964 citations recorded by the source corpus.

Internal bases in mRNA can be subjected to modifications that influence the fate of mRNA in cells. One of the most prevalent modified bases is found at the 5′ end of mRNA, at the first encoded nucleotide adjacent to the 7-methylguanosine cap. Here we show that this nucleotide, N6,2′-O-dimethyladenosine (m6Am), is a reversible modification that influences cellular mRNA fate. Using a transcriptome-wide map of m6Am we find that m6Am-initiated transcripts are markedly more stable than mRNAs that begin with other nucleotides. We show that the enhanced stability of m6Am-initiated transcripts is due to resistance to the mRNA-decapping enzyme DCP2. Moreover, we find that m6Am is selectively demethylated by fat mass and obesity-associated protein (FTO). FTO preferentially demethylates m6Am rather than N6-methyladenosine (m6A), and reduces the stability of m6Am mRNAs. Together, these findings show that the methylation status of m6Am in the 5′ cap is a dynamic and reversible epitranscriptomic modification that determines mRNA stability.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/ee7f21d1d6014050545ecfb92a1aa423b6de2bcd

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In Molecular Biology

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Citations in the corpus

• The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal and leukemia cells (2017, neutral): “…diagram (1) enriched for m 6 A targets, (2) negatively enriched for transcripts upregulated after METTL3 depletion and (3) gene sets negatively enriched for transcripts with reduced translation efficiency in METTL3-depleted cells (For specific gene sets see Supplementary Tables 5, 6, 9 and 10).”
• Where, when and how: context-dependent functions of RNA methylation writers, readers, and erasers (2019, background): “Cap m6Am was also proposed to promote translation efficiency of m6Am-containing mRNA with the FTO knockdown leading to decreased translation of several target genes (Mauer et al., 2017).”
• m6A RNA methylation: from mechanisms to therapeutic potential (2021, positive): “Since these initial reports, other substrates have since been reported and FTO has been shown to demethylate m 6 A, m 6 A m on mRNA, m 6 A m on U2 snRNA, and m 1 A on tRNA (Mauer et al , 2017, 2019; Wei et al , 2018).”
• Rethinking m6A Readers, Writers, and Erasers (2017, background): “In light of recent discoveries showing that m6Am has marked effects on mRNA stability and is selectively targeted for demethylation by FTO (Mauer et al. 2017), it is critical to have methods for distinguishing between the highly similar m6A and m6Am modifications when global analyses are performed.”
• METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m6A Modification (2017, background): “Nevertheless, METTL3-METTL14 complex does not mediate the cap m6Am methylation (Mauer et al., 2017).”