m6A Facilitates eIF4F-Independent mRNA Translation

Abstract

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.

Real-time 2-5A kinetics suggest that interferons β and λ evade global arrest of translation by RNase L

“…Translation of messenger RNAs also can benefit from m6A epigenetic markers in the 5′-UTR. Under conditions of global translational inhibition, m6A marks can facilitate initiation independent of the 5′-cap and internal ribosomal entry sites, prioritizing the translation of stress proteins (49,50).…”

Translation acrobatics: how cancer cells exploit alternate modes of translational initiation

“…Recent work has found that m 6 A methylation of mRNA occurs predominantly in the nucleus prior to mRNA splicing , suggesting that such regulation in response to stress would need to happen during mRNA biogenesis. Depletion of the methyltransferase METTL3 or of the m 6 A reader protein YTHDF1 selectively inhibits the translation of mRNAs bearing m 6 A modification, indicating that m 6 A modification plays an important role in mRNA translation .…”

A dynamic reversible RNA N6‐methyladenosine modification: current status and perspectives

“…m 6 A is also involved in translation. m 6 A facilitates eIF4F‐independent translation in mRNA (Coots et al, ). YTHDF1 has been implicated in the control of translation through an interaction with the eIF3 initiation factor (Wang et al, ).…”