title: 5' UTR m(6)A Promotes Cap-Independent Translation.
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.
authors.affiliation: Department of Pharmacology, Weill Medical College, Cornell University, New York, NY 10065, USA.
authors.forename: Kate D
authors.initials: KD
authors.lastname: Meyer
authors.affiliation: Department of Pharmacology, Weill Medical College, Cornell University, New York, NY 10065, USA.
authors.forename: Deepak P
authors.initials: DP
authors.lastname: Patil
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Cell Biology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zinoviev
authors.affiliation: Department of Cell Biology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
authors.forename: Maxim A
authors.initials: MA
authors.lastname: Skabkin
authors.affiliation: Department of Physiology and Biophysics, Weill Medical College, Cornell University, New York, NY 10065, USA; HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Medical College, Cornell University, New York, NY 10065, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Department of Cell Biology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
authors.forename: Tatyana V
authors.initials: TV
authors.lastname: Pestova
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Shu-Bing
authors.initials: SB
authors.lastname: Qian
authors.affiliation: Department of Pharmacology, Weill Medical College, Cornell University, New York, NY 10065, USA. Electronic address: srj2003@med.cornell.edu.
authors.forename: Samie R
authors.initials: SR
authors.lastname: Jaffrey
mesh_terms: D020121:5' Untranslated Regions; D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D004622:Embryo, Mammalian / Q000378:metabolism; D039621:Eukaryotic Initiation Factor-3 / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D010442:Peptide Chain Initiation, Translational; D014176:Protein Biosynthesis; D012270:Ribosomes / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; D039621:Eukaryotic Initiation Factor-3; D039561:Eukaryotic Initiation Factor-4E; D050884:HSP72 Heat-Shock Proteins; C010223:N-methyladenosine; D000241:Adenosine