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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
Author(s) -
Hatano Masaya,
Umemura Mariko,
Kimura Natsumi,
Yamazaki Takashi,
Takeda Hitoshi,
Nakano Haruo,
Takahashi Shigeru,
Takahashi Yuji
Publication year - 2013
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12440
Subject(s) - untranslated region , messenger rna , nonsense mediated decay , gene knockdown , upstream open reading frame , p bodies , five prime untranslated region , microbiology and biotechnology , biology , rna , translation (biology) , chemistry , gene , genetics , rna splicing
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.