5′ UTR m6A Promotes Cap-Independent Translation

By Kate D. Meyer, D. P. Patil, Jun Zhou, A. Zinoviev, M. Skabkin, Olivier Elemento, T. Pestova, Shu‐Bing Qian, Samie R. Jaffrey. Cell, 2015

1,307 citations recorded by the source corpus.

SUMMARY Protein translation typically begins with the recruitment of the 43S ribosomal complex to the 5′ cap of mRNAs by a cap-binding complex. However, some transcripts are translated in a cap-independent manner through poorly understood mechanisms. Here, we show that mRNAs containing N6-methyladenosine (m6A) in their 5′ UTR can be translated in a cap-independent manner. A single 5′ UTR m6A directly binds eukaryotic initiation factor 3 (eIF3), which is sufficient to recruit the 43S complex to initiate translation in the absence of the cap-binding factor eIF4E. Inhibition of adenosine methylation selectively reduces translation of mRNAs containing 5′UTR m6A. Additionally, increased m6A levels in the Hsp70 mRNA regulate its cap-independent translation following heat shock. Notably, we find that diverse cellular stresses induce a transcriptome-wide redistribution of m6A, resulting in increased numbers of mRNAs with 5′ UTR m6A. These data show that 5′ UTR m6A bypasses 5′ cap-binding proteins to promote translation under stresses.

Subfields: Electrical and Electronic Engineering, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3b0136693374ddc0306cdb2acd8c4d3396a672b1

Citations in the corpus

• Translational Control in Cancer. (2018, neutral): “Furthermore, IRESs, mRNA methylation, and a variety of noncanonical mechanisms of translation initiation maintain protein synthesis in the face of various stresses that inhibit cap-dependent translation (Meyer et al. 2015; Zhou et al. 2015a; Lacerda et al. 2017; Robichaud and Sonenberg 2017).”
• YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs (2017, neutral): “Additional roles in m6A-based regulation of cap-independent translation have been described for eIF3 as well as for the catalytic methyltransferase component METTL3, each functioning to promote the translation of methylated mRNAs (Lin et al., 2016; Meyer et al., 2015).”
• N 6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein (2017, neutral): “In addition to HNRNPC, other m6A reader proteins lacking a YTH domain have been shown to regulate pri-miRNA processing and mRNA translation (21,22).”
• Zc3h13 regulates nuclear RNA m6A methylation and mouse embryonic stem cell self-renewal (2018, neutral): “At the molecular level, m6A has been demonstrated to regulate RNA stability, translation, splicing and export (Meyer et al., 2015; Sommer et al., 1978; Wang et al., 2014a; Wang et al., 2015; Xiao et al., 2016).”
• RNA modifications modulate gene expression during development (2018, neutral): “For example, YTHDF2 binds to m 6 A in mRNA and targets the transcripts for degradation ( 3, 8 ), and YTHDF1, YTHDF3 and eIF3a promote translation of m 6 A containing transcripts ( 3, 9, 10 ).”
• METTL3 promotes translation in human cancer cells (2016, neutral): “Most recently, two papers reported that dynamic m(6)A modification in the 50 UTR of certain mRNAs promotes stress-induced translation (Meyer et al., 2015; Zhou et al., 2015).”
• Translation and functional roles of circular RNAs in human cancer (2020, neutral): “So, 5′ UTR methylation in the form of m6A acts as a dynamic regulator in alternative translation [78].”
• Circ-ZNF609 Is a Circular RNA that Can Be Translated and Functions in Myogenesis (2017, neutral): “This is the case of N6-methyladenosine (m6A) residues whose levels in 50 UTRs are increased upon different cellular stresses (Zhou et al., 2015; Meyer et al., 2015).”
• The potential role of RNA N6-methyladenosine in Cancer progression (2020, neutral): “m6A in the 5′ UTR region of transcripts can also directly recruit eIF3, which can recruit the 43S ribosomal preinitiation complex to promote cap-independent translation [41].”