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eIF3 interacts with histone H4 messenger RNA to regulate its translation

Abstract : In eukaryotes, translation initiation requires multiple complexes of eukaryotic initiation factors (eIFs) to assemble elongation-competent ribosomes to the mRNA. Such complexes trigger mRNA attachment to the small 40S ribosomal subunit, mRNA scanning and start codon selection as well as the assembly of the ribosome. Various alternative translation initiation mechanisms have been unveiled in eukaryotes for the translation of specific mRNAs. Some do not conform to the conventional scanning-initiation model. Translation initiation of histone H4 mRNA combines both canonical (cap-dependent) and viral initiation strategies (no-scanning, internal recruitment of initiation factors) (Martin et al. Mol. Cell, 2011). Specific H4 mRNA structures tether the translation machinery directly onto the initiation codon and allow massive production of histone H4 during the S phase of the cell cycle. The human eukaryotic translation initiation factor 3 (eIF3), composed of 13 subunits (a-m), was shown to selectively recruit and control the expression of several cellular mRNAs (Lee et al., 2015). We have studied the eIF3-H4 mRNA interaction in order to decipher its role in the translation of H4 mRNA. Here, we report that eIF3 binds to a stem-loop structure (eIF3-BS) located in the coding region of H4 mRNA. Combining cross-linking and ribonucleoprotein immunoprecipitation experiments in vivo and in vitro, we also found that eIF3 binds to H1, H2A, H2B, and H3 histone mRNAs. We identified direct contacts between eIF3c, d, e, g subunits, and histone mRNAs but observed distinct interaction patterns to each histone mRNA. To decipher the functional role of eIF3 we depleted individual eIF3 subunits in vivo by siRNA interference in G1/S synchronized cells. Our results show that depletion of eIF3 in vivo reduces histone mRNA binding and modulates histone neosynthesis monitored by [35S] pulse labeling, suggesting that histone synthesis is sensitive to the levels of eIF3. Thus, we provide evidence that eIF3 acts as a regulator of histone translation (Hayek et al. 2021). Martin F., Barends S., Jaeger S., Schaeffer L., Prongidi-Fix L., Eriani G. (2011) 41, 197-209. Lee AS., Kranzusch P., Cate J. (2015) Nature, 522, 111-114 Hayek H., Gross L., Janvier A., Schaeffer L., Martin F., Eriani G. and Allmang C. (2021) J. Biol. Chem., 296, 100578.
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https://hal-cnrs.archives-ouvertes.fr/hal-03564351
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Submitted on : Thursday, February 10, 2022 - 1:47:05 PM
Last modification on : Thursday, February 24, 2022 - 3:24:00 AM

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Hassan Hayek, Lauriane Gross, Aurélie Janvier, Laure Schaeffer, Franck Martin, et al.. eIF3 interacts with histone H4 messenger RNA to regulate its translation. 2021 RiboClub Program Transcriptomics and cancer biology, Sep 2021, Sherbrooke, Canada. ⟨hal-03564351⟩

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