RT Journal
A1 Gandin, Valentina
A1 Masvidal, Laia
A1 Hulea, Laura
A1 Gravel, Simon-Pierre
A1 Cargnello, Marie
A1 McLaughlan, Shannon
A1 Cai, Yutian
A1 Balanathan, Preetika
A1 Morita, Masahiro
A1 Rajakumar, Arjuna
A1 Furic, Luc
A1 Pollak, Michael
A1 Porco, John A.
A1 St-Pierre, Julie
A1 Pelletier, Jerry
A1 Larsson, Ola
A1 Topisirovic, Ivan
T1 nanoCAGE reveals 5′ UTR features that define specific modes of translation of functionally related MTOR-sensitive mRNAs
JF Genome Research 
JO Genome Research 
YR 2016 
FD May 01 
VO 26 
IS 5 
SP 636 
OP 648 
DO 10.1101/gr.197566.115 
UL http://genome.cshlp.org/content/26/5/636.abstract 
AB 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.