Dataset Information

EIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5'UTR.

ABSTRACT: 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.

SUBMITTER: Wilczynska A

PROVIDER: S-EPMC6886185 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5'UTR.

Wilczynska Ania A Gillen Sarah L SL Schmidt Tobias T Meijer Hedda A HA Jukes-Jones Rebekah R Langlais Claudia C Kopra Kari K Lu Wei-Ting WT Godfrey Jack D JD Hawley Benjamin R BR Hodge Kelly K Zanivan Sara S Cain Kelvin K Le Quesne John J Bushell Martin M

Genome biology 20191202 1

<h4>Background</h4>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.<h4>Results</h4>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 ...[more]

PMID: 31791371

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Project description:BACKGROUND: Utilization of alternative initiation sites for protein translation directed by non-AUG codons in mammalian mRNAs is observed with increasing frequency. Alternative initiation sites are utilized for the synthesis of important regulatory proteins that control distinct biological functions. It is, therefore, of high significance to define the parameters that allow accurate bioinformatic prediction of alternative translation initiation sites (aTIS). This study has investigated 5'-UTR regions of mRNAs to define consensus sequence properties and structural features that allow identification of alternative initiation sites for protein translation. RESULTS: Bioinformatic evaluation of 5'-UTR sequences of mammalian mRNAs was conducted for classification and identification of alternative translation initiation sites for a group of mRNA sequences that have been experimentally demonstrated to utilize alternative non-AUG initiation sites for protein translation. These are represented by the codons CUG, GUG, UUG, AUA, and ACG for aTIS. The first phase of this bioinformatic analysis implements a classification tree that evaluated 5'-UTRs for unique consensus sequence features near the initiation codon, characteristics of 5'-UTR nucleotide sequences, and secondary structural features in a decision tree that categorizes mRNAs into those with potential aTIS, and those without. The second phase addresses identification of the aTIS codon and its location. Critical parameters of 5'-UTRs were assessed by an Artificial Neural Network (ANN) for identification of the aTIS codon and its location. ANNs have previously been used for the purpose of AUG start site prediction and are applicable in complex. ANN analyses demonstrated that multiple properties were required for predicting aTIS codons; these properties included unique consensus nucleotide sequences at positions -7 and -6 combined with positions -3 and +4, 5'-UTR length, ORF length, predicted secondary structures, free energy features, upstream AUGs, and G/C ratio. Importantly, combined results of the classification tree and the ANN analyses provided highly accurate bioinformatic predictions of alternative translation initiation sites. CONCLUSION: This study has defined the unique properties of 5'-UTR sequences of mRNAs for successful bioinformatic prediction of alternative initiation sites utilized in protein translation. The ability to define aTIS through the described bioinformatic analyses can be of high importance for genomic analyses to provide full predictions of translated mammalian and human gene products required for cellular functions in health and disease.

Dataset Information

EIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5'UTR.

Publications

eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5'UTR.

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