YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA

Shi, Hailing; Xiao, Wang; Lu, Zhike; Zhao, Boxuan Simen; Ma, Honghui; Hsu, Phillip J.; Liu, Chang; He, Chuan

doi:10.1038/cr.2017.15

Cited by 1,257 publications

(1,189 citation statements)

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“…Given the plasticity of the HIV-1 genome, this conservation clearly implies that m 6 A facilitates some aspect of the replication cycle of HIV-1 and, by extension, of other nuclear viruses that express m 6 A-modified transcripts (Table 1). We note that m 6 A addition has been proposed to affect mRNA splicing (24)(25)(26), stability (27,47), and translation (47)(48)(49)(50), to modify RNA structure (51), and to inhibit the recognition of viral RNAs by Toll-like receptors and RIG-I (52, 53), and so m 6 A could positively regulate several aspects of the viral life cycle. Indeed, knockdown of the METTL3 and/or METTL14 m 6 A writers using RNA interference (RNAi) has been reported to inhibit HIV-1 replication up to 5-fold, while knockdown of the ALKBH5 m 6 A demethylase enhanced HIV-1 replication up to 8-fold (11,14).…”

Section: Nuclear Rna and Dna Virusesmentioning

confidence: 99%

Viral Epitranscriptomics

Kennedy

Courtney

Tsai

et al. 2017

J Virol

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Although it has been known for over 40 years that eukaryotic mRNAs bear internal base modifications, it is only in the last 5 years that the importance of these modifications has begun to come into focus. The most common mRNA modification, the addition of a methyl group to the N 6 position of adenosine (m 6 A), has been shown to affect splicing, translation, and stability, and m 6 A is also essential for embryonic development in organisms ranging from plants to mice. While all viral transcripts examined so far have been found to be extensively m 6 A modified, the role, if any, of m 6 A in regulating viral gene expression and replication was previously unknown. However, recent data generated using HIV-1 as a model system strongly suggest that sites of m 6 A addition not only are evolutionarily conserved but also enhance virus replication. It is therefore likely that the field of viral epitranscriptomics, which can be defined as the study of functionally relevant posttranscriptional modifications of viral RNA transcripts that do not change the nucleotide sequence of that RNA, is poised for a major expansion in scientific interest and may well fundamentally change our understanding of how viral replication is regulated.KEYWORDS Posttranscriptional gene regulation, RNA modification, N 6 -methyladenosine, mRNA function, mRNA stability, HIV-1 W hile over 100 different modified bases have been identified on RNA transcripts in mammalian cells, the majority of these are restricted to noncoding RNAs, especially tRNAs. However, at least 10 distinct modified bases have now been reported to occur in mammalian mRNAs (1). In addition to the 7-methylguanosine cap that is added at the 5= end of all cellular mRNAs, these include N 6 -methyladenosine (m 6 A), 2=-Omethyladenosine (Am), N 6 -2=-O-methyladenosine (m 6 Am), pseudouridine, and 5-methylcytosine. Of these, by far the most prevalent internal modified base found on mRNAs is m 6 A, and recent work has now begun to reveal how m 6 A affects mRNA function and how to precisely map the m 6 A residues present on mRNAs (1-3). m 6 A is also highly prevalent on a wide range of different viral RNA species (4-13), and recently, the first reports demonstrating a significant phenotypic effect of these m 6 A modifications have been published (10-14). Therefore, we will focus this review entirely on m 6 A and how this particular modification might affect different aspects of the viral life cycle. m 6 A was first reported to be present on cellular mRNAs in 1975 with ϳ3 internal m 6 A residues found on the average ϳ2.2-kb transcript (15, 16). However, we now know that many cellular mRNAs, including mRNAs encoding housekeeping genes, lack any m 6 A residues, while highly regulated mRNAs may contain 10 or more (2, 3). The first demonstration of m 6 A residues on viral mRNAs soon followed and, using the biochemical approaches available at that time, a range of mRNAs encoded by several nuclear DNA and RNA viruses were then shown to bear fairly high levels of m 6 A, with the eight influ...

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Section: Nuclear Rna and Dna Virusesmentioning

confidence: 99%

Viral Epitranscriptomics

Kennedy

Courtney

Tsai

et al. 2017

J Virol

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“…Previous work has shown that the YTH domain is a specific ‘m 6 A-reader’ domain 9 , suggesting that YTH-domain-containing proteins act as effectors of m 6 A in cells. Indeed, recent studies have revealed a role for YTH-domain-containing proteins in the regulation of various aspects of mRNA homeostasis: YTHDF2 regulates mRNA stability 19 , YTHDC1 regulates splicing 24 , and YTHDF1 and YTHDF3 regulate translation 22,27 . In addition to YTH-domain-containing proteins, HNRNP proteins have also been shown to recognize m 6 A 28–30 .…”

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confidence: 99%

N6-methyladenosine (m6A) recruits and repels proteins to regulate mRNA homeostasis

Edupuganti

Geiger

Lindeboom

et al. 2017

Nat Struct Mol Biol

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434

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RNA modifications are integral to the regulation of RNA metabolism. One abundant mRNA modification is N6-methyladenosine (m6A), which affects various aspects of RNA metabolism, including splicing, translation and degradation. Current knowledge about the proteins recruited to m6A to carry out these molecular processes is still limited. Here we describe comprehensive and systematic mass-spectrometry-based screening of m6A interactors in various cell types and sequence contexts. Among the main findings, we identified G3BP1 as a protein that is repelled by m6A and positively regulates mRNA stability in an m6A-regulated manner. Furthermore, we identified FMR1 as a sequence-context-dependent m6A reader, thus revealing a connection between an mRNA modification and an autism spectrum disorder. Collectively, our data represent a rich resource and shed further light on the complex interplay among m6A, m6A interactors and mRNA homeostasis.

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“…Recently, m 6 A mRNA modification has been shown to be important for the stability and translational efficiency of mRNA (Wang et al 2014aDu et al 2016;Li et al 2017;Shi et al 2017). m 6 A methylation is a post-transcriptional modification of mRNA occurring in the nucleus (Lee et al 2014;Ping et al 2014).…”

Section: Introductionmentioning

confidence: 99%

N⁶-methyladenosine is required for the hypoxic stabilization of specific mRNAs

Fry

Law

Ilkayeva

et al. 2017

RNA

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Post-transcriptional regulation of mRNA during oxygen deprivation, or hypoxia, can affect the survivability of cells. Hypoxia has been shown to increase stability of a subset of ischemia-related mRNAs, including VEGF. RNA binding proteins and miRNAs have been identified as important for post-transcriptional regulation of individual mRNAs, but corresponding mechanisms that regulate global stability are not well understood. Recently, mRNA modification by N 6 -methyladenosine (m 6 A) has been shown to be involved in post-transcriptional regulation processes including mRNA stability and promotion of translation, but the role of m 6 A in the hypoxia response is unknown. In this study, we investigate the effect of hypoxia on RNA modifications including m 6 A. Our results show hypoxia increases m 6 A content of poly(A) + messenger RNA (mRNA), but not in total or ribosomal RNA in HEK293T cells. Using m 6 A mRNA immunoprecipitation, we identify specific hypoxia-modified mRNAs, including glucose transporter 1 (Glut1) and c-Myc, which show increased m 6 A levels under hypoxic conditions. Many of these mRNAs also exhibit increased stability, which was blocked by knockdown of m 6 A-specific methyltransferases METTL3/14. However, the increase in mRNA stability did not correlate with a change in translational efficiency or the steady-state amount of their proteins. Knockdown of METTL3/14 did reveal that m 6 A is involved in recovery of translational efficiency after hypoxic stress. Therefore, our results suggest that an increase in m 6 A mRNA during hypoxic exposure leads to post-transcriptional stabilization of specific mRNAs and contributes to the recovery of translational efficiency after hypoxic stress.

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YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA

Cited by 1,257 publications

References 53 publications

Viral Epitranscriptomics

Viral Epitranscriptomics

N6-methyladenosine (m6A) recruits and repels proteins to regulate mRNA homeostasis

N⁶-methyladenosine is required for the hypoxic stabilization of specific mRNAs

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YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA

Cited by 1,257 publications

References 53 publications

Viral Epitranscriptomics

Viral Epitranscriptomics

N6-methyladenosine (m6A) recruits and repels proteins to regulate mRNA homeostasis

N6-methyladenosine is required for the hypoxic stabilization of specific mRNAs

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N⁶-methyladenosine is required for the hypoxic stabilization of specific mRNAs