5' UTR m(6)A Promotes Cap-Independent Translation

Cell. 2015 Nov 5;163(4):999-1010. doi: 10.1016/j.cell.2015.10.012. Epub 2015 Oct 22.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 5' Untranslated Regions
  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Animals
  • Embryo, Mammalian / metabolism
  • Eukaryotic Initiation Factor-3 / metabolism
  • Eukaryotic Initiation Factor-4E / metabolism
  • Fibroblasts / metabolism
  • HSP72 Heat-Shock Proteins / metabolism
  • HeLa Cells
  • Humans
  • Mice
  • Peptide Chain Initiation, Translational*
  • Protein Biosynthesis*
  • Ribosomes / metabolism

Substances

  • 5' Untranslated Regions
  • Eukaryotic Initiation Factor-3
  • Eukaryotic Initiation Factor-4E
  • HSP72 Heat-Shock Proteins
  • N6-methyladenosine (m6A)
  • Adenosine

Associated data

  • GEO/GSE73405