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

Title5' UTR m(6)A Promotes Cap-Independent Translation.
Publication TypeJournal Article
Year of Publication2015
AuthorsMeyer KD, Patil DP, Zhou J, Zinoviev A, Skabkin MA, Elemento O, Pestova TV, Qian S-B, Jaffrey SR
JournalCell
Volume163
Issue4
Pagination999-1010
Date Published2015 Nov 05
ISSN1097-4172
Keywords5' Untranslated Regions, Adenosine, Animals, Embryo, Mammalian, Eukaryotic Initiation Factor-3, Eukaryotic Initiation Factor-4E, Fibroblasts, HeLa Cells, HSP72 Heat-Shock Proteins, Humans, Mice, Peptide Chain Initiation, Translational, Protein Biosynthesis, Ribosomes
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.

DOI10.1016/j.cell.2015.10.012
Alternate JournalCell
PubMed ID26593424
PubMed Central IDPMC4695625
Grant ListR01 GM059660 / GM / NIGMS NIH HHS / United States
T32 CA062948 / CA / NCI NIH HHS / United States
K99MH104712 / MH / NIMH NIH HHS / United States
R01 CA186702 / CA / NCI NIH HHS / United States
R01 AG042400 / AG / NIA NIH HHS / United States
K99 MH104712 / MH / NIMH NIH HHS / United States
R01DA037755 / DA / NIDA NIH HHS / United States
GM59660 / GM / NIGMS NIH HHS / United States
AG042400 / AG / NIA NIH HHS / United States
R01 DA037755 / DA / NIDA NIH HHS / United States