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2016 ; 291
(20
): 10824-35
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Translation Regulation of the Glutamyl-prolyl-tRNA Synthetase Gene EPRS through
Bypass of Upstream Open Reading Frames with Noncanonical Initiation Codons
#MMPMID27002157
Young SK
; Baird TD
; Wek RC
J Biol Chem
2016[May]; 291
(20
): 10824-35
PMID27002157
show ga
In the integrated stress response, phosphorylation of eIF2? (eIF2?-P) reduces
protein synthesis while concomitantly promoting preferential translation of
specific transcripts associated with stress adaptation. Translation of the
glutamyl-prolyl-tRNA synthetase gene EPRS is enhanced in response to eIF2?-P. To
identify the underlying mechanism of translation control, we employed biochemical
approaches to determine the regulatory features by which upstream ORFs (uORFs)
direct downstream translation control and expression of the EPRS coding region.
Our findings reveal that translation of two inhibitory uORFs encoded by
noncanonical CUG and UUG initiation codons in the EPRS mRNA 5'-leader serve to
dampen levels of translation initiation at the EPRS coding region. By a mechanism
suggested to involve increased translation initiation stringency during
stress-induced eIF2?-P, we observed facilitated ribosome bypass of these uORFs,
allowing for increased translation of the EPRS coding region. Importantly, EPRS
protein expression is enhanced through this preferential translation mechanism in
response to multiple known activators of eIF2?-P and likely serves to facilitate
stress adaptation in response to a variety of cellular stresses. The rules
presented here for the regulated ribosome bypass of noncanonical initiation
codons in the EPRS 5'-leader add complexity into the nature of uORF-mediated
translation control mechanisms during eIF2?-P and additionally illustrate the
roles that previously unexamined uORFs with noncanonical initiation codons can
play in modulating gene expression.