Cytoplasmic m6A reader YTHDF3 promotes mRNA translation

Li, Ang; Chen, Yu‐Sheng; Ping, Xiao-Li; Yang, Xin; Xiao, Wen; Yang, Ying; Sun, Hui; Zhu, Qin; Baidya, Poonam; Wang, Xing; Bhattarai, Devi Prasad; Zhao, Yongliang; Sun, Bao‐Fa

doi:10.1038/cr.2017.10

Cited by 659 publications

(677 citation statements)

References 14 publications

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“…Interestingly, knocking down YTHDF3, but not YTHDF1 and YTHDF2, re-sensitized MEF cells to Torin1 treatment (Figure S5A). The putative role of YTHDF3 in eIF4F-independent translation is consistent with several recent studies reporting that YTHDF3 facilitated mRNA translation, including m 6 A-mediated circular RNA translation (Li et al, 2017; Shi et al, 2017; Yang et al, 2017). …”

Section: Resultssupporting

confidence: 90%

m6A Facilitates eIF4F-Independent mRNA Translation

et al. 2017

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SUMMARY In eukaryotic cells, protein synthesis typically begins with the binding of eIF4F to the 7-methylguanylate (m7G) cap found on the 5’ end of the majority of mRNAs. Surprisingly, overall translational output remains robust under eIF4F inhibition. The broad spectrum of eIF4F-resistant translatomes is incompatible with cap-independent translation mediated by internal ribosome entry sites (IRES). Here, we report that N6-methyladenosine (m6A) facilitates mRNA translation that is resistant to eIF4F inactivation. Depletion of the methyltransferase METTL3 selectively inhibits translation of mRNAs bearing 5’UTR methylation, but not mRNAs with 5’ terminal oligopyrimidine (TOP) elements. We identify ABCF1 as a critical mediator of m6A-promoted translation under both stress and physiological conditions. Supporting the role of ABCF1 in m6A-facilitated mRNA translation, ABCF1-sensitive transcripts largely overlap with METTL3-dependent mRNA targets. By illustrating the scope and mechanism of eIF4F-independent mRNA translation, these findings reshape our current perceptions of cellular translational pathways.

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Section: Resultssupporting

confidence: 90%

m6A Facilitates eIF4F-Independent mRNA Translation

et al. 2017

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“…Both m 6 A at the 5’ UTR and m 6 Am near the cap appear to correlate with increased translation. YTHDF3 mediates translation along with YTHDF1 by interaction with a common set of ribosomal proteins, as well as decay of mRNA targets by associating directly with YTHDF2 (Li et al, 2017a; Shi et al, 2017), and may play additional cell-type specific roles and functions based on m 6 A location within transcripts.…”

Section: Properties Of Mrna Modifications – Structure and Functionmentioning

confidence: 99%

Dynamic RNA Modifications in Gene Expression Regulation

Roundtree

Evans

Pan

et al. 2017

Cell

2,450

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Over one hundred types of chemical modifications have been identified in cellular RNAs. While the 5’ cap modification and the poly(A) tail of eukaryotic messenger RNA play key roles in regulation, internal modifications are gaining attention for their roles in mRNA metabolism. The most abundant internal modification is N6-methyladenosine (m6A), and identification of proteins that install, recognize, and remove this and other marks have revealed roles for mRNA modification in nearly every aspect of the mRNA lifecycle, as well as in various cellular, developmental, and disease processes. Abundant noncoding RNAs such as transfer RNAs, ribosomal RNAs and spliceosomal RNAs are also heavily modified and depend on the modifications for their biogenesis and function. Our understanding of the biological contributions of these different chemical modifications is beginning to take shape, but it’s clear that in both coding and noncoding RNA, dynamic modifications represent a new layer of control of genetic information.

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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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Cytoplasmic m6A reader YTHDF3 promotes mRNA translation

Cited by 659 publications

References 14 publications

m6A Facilitates eIF4F-Independent mRNA Translation

m6A Facilitates eIF4F-Independent mRNA Translation

Dynamic RNA Modifications in Gene Expression Regulation

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

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Cytoplasmic m6A reader YTHDF3 promotes mRNA translation

Cited by 659 publications

References 14 publications

m6A Facilitates eIF4F-Independent mRNA Translation

m6A Facilitates eIF4F-Independent mRNA Translation

Dynamic RNA Modifications in Gene Expression Regulation

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