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The 5′‐untranslated region regulates ATF 5 m RNA stability via nonsense‐mediated m RNA decay in response to environmental stress
Ist Teil von
The FEBS journal, 2013-09, Vol.280 (18), p.4693-4707
Erscheinungsjahr
2013
Quelle
Wiley-Blackwell Journals
Beschreibungen/Notizen
We previously reported that activating transcription factor 5 (
ATF
5) m
RNA
increases in response to amino acid limitation, and that this increase is dependent on m
RNA
stabilization. The
ATF
5
gene allows transcription of m
RNA
s with two alternative 5′‐
UTR
s, 5′‐
UTR
α and 5′‐
UTR
β, derived from exon 1α and exon 1β. 5′‐
UTR
α contains the upstream open reading frames u
ORF
1 and u
ORF
2. Phosphorylation of eukaryotic initiation factor 2α during the integrated stress response had been previously shown to lead to bypassing of u
ORF
2 translation and production of
ATF
5 protein. Translation of u
ORF
2 is expected to result in translational termination at a position 125 nucleotides upstream of the exon junction, and this fits the criterion of a nonsense‐mediated decay target m
RNA
. We investigated the potential role of 5′‐
UTR
α in the control of m
RNA
stabilization, and found that 5′‐
UTR
α reduced the stability of
ATF
5 m
RNA
. 5′‐
UTR
α‐regulated destabilization of m
RNA
was suppressed by knockdown of the nonsense‐mediated decay factors
U
pf1 and
U
pf2. Mutation of the downstream
AUG
(u
AUG
2) rendered m
RNA
refractory to Upf1 and Upf2 knockdown. Moreover, 5′‐
UTR
α‐regulated down‐regulation was hindered by amino acid limitation and tunicamycin treatment, and stress‐induced phosphorylation of eukaryotic initiation factor 2α was involved in stabilization of
ATF
5 m
RNA
. These studies show that
ATF
5 m
RNA
is a naturally occurring normal m
RNA
target of nonsense‐mediated decay, and provide evidence for linkage between stress‐regulated translational regulation and the m
RNA
decay pathway. This linkage constitutes a mechanism that regulates expression of stress response genes.
Sprache
Englisch
Identifikatoren
ISSN: 1742-464X
eISSN: 1742-4658
DOI: 10.1111/febs.12440
Titel-ID: cdi_crossref_primary_10_1111_febs_12440
Format
–
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