Charting DENR-dependent translation reinitiation uncovers predictive uORF features and links to circadian timekeeping via Clock.

Détails

Ressource 1Télécharger: gkz261.pdf (4837.07 [Ko])
Etat: Public
Version: Final published version
Licence: CC BY 4.0
Document(s) secondaire(s)
Télécharger: Supplementary_Figures_and_Legends.pdf (20343.16 [Ko])
Etat: Public
Version: Supplementary document
Licence: Non spécifiée
ID Serval
serval:BIB_9D401C4DBF9B
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Charting DENR-dependent translation reinitiation uncovers predictive uORF features and links to circadian timekeeping via Clock.
Périodique
Nucleic acids research
Auteur(s)
Castelo-Szekely V., De Matos M., Tusup M., Pascolo S., Ule J., Gatfield D.
ISSN
1362-4962 (Electronic)
ISSN-L
0305-1048
Statut éditorial
Publié
Date de publication
04/06/2019
Peer-reviewed
Oui
Volume
47
Numéro
10
Pages
5193-5209
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
The non-canonical initiation factor DENR promotes translation reinitiation on mRNAs harbouring upstream open reading frames (uORFs). Moreover, DENR depletion shortens circadian period in mouse fibroblasts, suggesting involvement of uORF usage and reinitiation in clock regulation. To identify DENR-regulated translation events transcriptome-wide and, in particular, specific core clock transcripts affected by this mechanism, we have used ribosome profiling in DENR-deficient NIH3T3 cells. We uncovered 240 transcripts with altered translation rate, and used linear regression analysis to extract 5' UTR features predictive of DENR dependence. Among core clock genes, we identified Clock as a DENR target. Using Clock 5' UTR mutants, we mapped the specific uORF through which DENR acts to regulate CLOCK protein biosynthesis. Notably, these experiments revealed an alternative downstream start codon, likely representing the bona fide CLOCK N-terminus. Our findings provide insights into uORF-mediated translational regulation that can regulate the mammalian circadian clock and gene expression at large.
Mots-clé
5' Untranslated Regions, Animals, CLOCK Proteins/genetics, CLOCK Proteins/metabolism, Circadian Rhythm, Cloning, Molecular, Codon, Initiator, Eukaryotic Initiation Factors/genetics, Eukaryotic Initiation Factors/metabolism, Fibroblasts/metabolism, Gene Expression Regulation, HEK293 Cells, Humans, Luciferases/metabolism, Mice, Mutation, NIH 3T3 Cells, Open Reading Frames, RNA, Messenger/metabolism, Ribosomes/metabolism
Pubmed
Web of science
Open Access
Oui
Financement(s)
Fonds national suisse / Carrières / PP00P3_157528
Fonds national suisse / Projets / 31003A_179190
Université de Lausanne
Création de la notice
11/06/2019 12:37
Dernière modification de la notice
16/12/2019 7:19
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