title: nanoCAGE reveals 5' UTR features that define specific modes of translation of functionally related MTOR-sensitive mRNAs.
abstract: The diversity of MTOR-regulated mRNA translation remains unresolved. Whereas ribosome-profiling suggested that MTOR almost exclusively stimulates translation of the TOP (terminal oligopyrimidine motif) and TOP-like mRNAs, polysome-profiling indicated that MTOR also modulates translation of mRNAs without the 5' TOP motif (non-TOP mRNAs). We demonstrate that in ribosome-profiling studies, detection of MTOR-dependent changes in non-TOP mRNA translation was obscured by low sensitivity and methodology biases. Transcription start site profiling using nano-cap analysis of gene expression (nanoCAGE) revealed that not only do many MTOR-sensitive mRNAs lack the 5' TOP motif but that 5' UTR features distinguish two functionally and translationally distinct subsets of MTOR-sensitive mRNAs: (1) mRNAs with short 5' UTRs enriched for mitochondrial functions, which require EIF4E but are less EIF4A1-sensitive; and (2) long 5' UTR mRNAs encoding proliferation- and survival-promoting proteins, which are both EIF4E- and EIF4A1-sensitive. Selective inhibition of translation of mRNAs harboring long 5' UTRs via EIF4A1 suppression leads to sustained expression of proteins involved in respiration but concomitant loss of those protecting mitochondrial structural integrity, resulting in apoptosis. Conversely, simultaneous suppression of translation of both long and short 5' UTR mRNAs by MTOR inhibitors results in metabolic dormancy and a predominantly cytostatic effect. Thus, 5' UTR features define different modes of MTOR-sensitive translation of functionally distinct subsets of mRNAs, which may explain the diverse impact of MTOR and EIF4A inhibitors on neoplastic cells.
authors.affiliation: Lady Davis Institute, SMBD Jewish General Hospital, Montreal, Canada H3T 1E2; Department of Oncology, McGill University, Montreal, Canada H3G 1Y6; Department of Experimental Medicine, McGill University, Montreal, Canada H3G 1Y6; Department of Biochemistry, McGill University, Montreal, Canada H3G 1Y6;
authors.forename: Valentina
authors.initials: V
authors.lastname: Gandin
authors.affiliation: Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, 171 65 Solna, Sweden;
authors.forename: Laia
authors.initials: L
authors.lastname: Masvidal
authors.affiliation: Lady Davis Institute, SMBD Jewish General Hospital, Montreal, Canada H3T 1E2; Department of Oncology, McGill University, Montreal, Canada H3G 1Y6;
authors.forename: Laura
authors.initials: L
authors.lastname: Hulea
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Canada H3G 1Y6; Goodman Cancer Research Centre, McGill University, Montreal, Canada H3A 1A3;
authors.forename: Simon-Pierre
authors.initials: SP
authors.lastname: Gravel
authors.affiliation: Lady Davis Institute, SMBD Jewish General Hospital, Montreal, Canada H3T 1E2; Department of Oncology, McGill University, Montreal, Canada H3G 1Y6;
authors.forename: Marie
authors.initials: M
authors.lastname: Cargnello
authors.affiliation: Lady Davis Institute, SMBD Jewish General Hospital, Montreal, Canada H3T 1E2; Department of Oncology, McGill University, Montreal, Canada H3G 1Y6;
authors.forename: Shannon
authors.initials: S
authors.lastname: McLaughlan
authors.affiliation: Lady Davis Institute, SMBD Jewish General Hospital, Montreal, Canada H3T 1E2; Department of Biochemistry, McGill University, Montreal, Canada H3G 1Y6;
authors.forename: Yutian
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Cancer Program, Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Victoria 3800, Australia;
authors.forename: Preetika
authors.initials: P
authors.lastname: Balanathan
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Canada H3G 1Y6; Goodman Cancer Research Centre, McGill University, Montreal, Canada H3A 1A3;
authors.forename: Masahiro
authors.initials: M
authors.lastname: Morita
authors.affiliation: Lady Davis Institute, SMBD Jewish General Hospital, Montreal, Canada H3T 1E2;
authors.forename: Arjuna
authors.initials: A
authors.lastname: Rajakumar
authors.affiliation: Cancer Program, Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Victoria 3800, Australia;
authors.forename: Luc
authors.initials: L
authors.lastname: Furic
authors.affiliation: Lady Davis Institute, SMBD Jewish General Hospital, Montreal, Canada H3T 1E2; Department of Oncology, McGill University, Montreal, Canada H3G 1Y6; Department of Experimental Medicine, McGill University, Montreal, Canada H3G 1Y6;
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
authors.affiliation: Center for Chemical Methodology and Library Development, Boston University, Boston, Massachusetts 02215, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Porco
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Canada H3G 1Y6; Goodman Cancer Research Centre, McGill University, Montreal, Canada H3A 1A3;
authors.forename: Julie
authors.initials: J
authors.lastname: St-Pierre
authors.affiliation: Department of Oncology, McGill University, Montreal, Canada H3G 1Y6; Department of Biochemistry, McGill University, Montreal, Canada H3G 1Y6; Goodman Cancer Research Centre, McGill University, Montreal, Canada H3A 1A3;
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
authors.affiliation: Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, 171 65 Solna, Sweden;
authors.forename: Ola
authors.initials: O
authors.lastname: Larsson
authors.affiliation: Lady Davis Institute, SMBD Jewish General Hospital, Montreal, Canada H3T 1E2; Department of Oncology, McGill University, Montreal, Canada H3G 1Y6; Department of Experimental Medicine, McGill University, Montreal, Canada H3G 1Y6; Department of Biochemistry, McGill University, Montreal, Canada H3G 1Y6;
authors.forename: Ivan
authors.initials: I
authors.lastname: Topisirovic
mesh_terms: D020121:5' Untranslated Regions / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D014176:Protein Biosynthesis / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D020121:5' Untranslated Regions; D039561:Eukaryotic Initiation Factor-4E; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases