eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5'UTR.
Journal
Genome biology
ISSN: 1474-760X
Titre abrégé: Genome Biol
Pays: England
ID NLM: 100960660
Informations de publication
Date de publication:
02 12 2019
02 12 2019
Historique:
received:
16
07
2019
accepted:
10
10
2019
entrez:
4
12
2019
pubmed:
4
12
2019
medline:
21
3
2020
Statut:
epublish
Résumé
Regulation of the mRNA life cycle is central to gene expression control and determination of cell fate. miRNAs represent a critical mRNA regulatory mechanism, but despite decades of research, their mode of action is still not fully understood. Here, we show that eIF4A2 is a major effector of the repressive miRNA pathway functioning via the Ccr4-Not complex. We demonstrate that while DDX6 interacts with Ccr4-Not, its effects in the mechanism are not as pronounced. Through its interaction with the Ccr4-Not complex, eIF4A2 represses mRNAs at translation initiation. We show evidence that native eIF4A2 has similar RNA selectivity to chemically inhibited eIF4A1. eIF4A2 exerts its repressive effect by binding purine-rich motifs which are enriched in the 5'UTR of target mRNAs directly upstream of the AUG start codon. Our data support a model whereby purine motifs towards the 3' end of the 5'UTR are associated with increased ribosome occupancy and possible uORF activation upon eIF4A2 binding.
Sections du résumé
BACKGROUND
Regulation of the mRNA life cycle is central to gene expression control and determination of cell fate. miRNAs represent a critical mRNA regulatory mechanism, but despite decades of research, their mode of action is still not fully understood.
RESULTS
Here, we show that eIF4A2 is a major effector of the repressive miRNA pathway functioning via the Ccr4-Not complex. We demonstrate that while DDX6 interacts with Ccr4-Not, its effects in the mechanism are not as pronounced. Through its interaction with the Ccr4-Not complex, eIF4A2 represses mRNAs at translation initiation. We show evidence that native eIF4A2 has similar RNA selectivity to chemically inhibited eIF4A1. eIF4A2 exerts its repressive effect by binding purine-rich motifs which are enriched in the 5'UTR of target mRNAs directly upstream of the AUG start codon.
CONCLUSIONS
Our data support a model whereby purine motifs towards the 3' end of the 5'UTR are associated with increased ribosome occupancy and possible uORF activation upon eIF4A2 binding.
Identifiants
pubmed: 31791371
doi: 10.1186/s13059-019-1857-2
pii: 10.1186/s13059-019-1857-2
pmc: PMC6886185
doi:
Substances chimiques
5' Untranslated Regions
0
CCR4 protein, human
0
CNOT1 protein, human
0
MicroRNAs
0
Receptors, CCR4
0
Transcription Factors
0
DEAD-box RNA Helicases
EC 3.6.4.13
EIF4A2 protein, human
EC 3.6.4.13
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
262Subventions
Organisme : Medical Research Council
ID : MC_UU_00025/6
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_EX_G0902052
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_A600_1024
Pays : United Kingdom
Organisme : British Heart Foundation
ID : BB/N017005/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A29252
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_1203/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : BB/M001865/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C596/A17196
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A17196
Pays : United Kingdom
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