5′ UTR m6A Promotes Cap-Independent Translation

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 N 6 -methyladenosine (m 6 A) in their 5′ UTR can be translated in a cap-independent manner. A single 5′ UTR m 6 A 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 m 6 A. Additionally, increased m 6 A 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 m 6 A, resulting in increased numbers of mRNAs with 5′ UTR m 6 A. These data show that 5′ UTR m 6 A bypasses 5′ cap-binding proteins to promote translation under stresses.