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Erythroid mRNA translation in RPS14 deficiency
ribosomes on the transcript and protein abundance usual- ly negatively correlates with the CDS length.49 In addi- tion, a high density of ribosomes on short transcripts con- tributes to the efficiency of their translation.47,48 Recent computational analyses have shown that the recycling/re- initiation process could account for the high density of ribosomes and efficient translation of short mRNAs.44,50 In our current study, the severe defect we observed in the translation of the shortest transcripts could be explained by a diminution of re-initiation. The same reasoning may explain why high CAI transcripts were more impacted by the limited ribosome availability than those with a low CAI. Under normal conditions, it has been shown that a high CAI is an advantage in terms of having access to this process of recycling/re-initiation due to a faster elonga- tion rate.44
In conclusion, the rate of protein synthesis depends on a complex network of regulatory elements that include expression levels of mRNAs, the cellular concentration of ribosomes, the mRNA length, the density of ribosomes, and the initiation and termination rates.4 Our current find- ings indicate that, when the ribosome concentration becomes a limiting factor, the translation is selective, and is dependent on the mRNA CAI, length and 3’UTR struc- ture. Further investigations are required to better under- stand how the cellular ribosome concentration modifies translation initiation, translation termination, and ribo- some recycling to create the link between the genetic alteration of an RP and impaired translation in erythroid cells.
Disclosures
No conflicts of interest to disclose.
Contributions
IB designed the study, performed the experiments, analyzed the data and wrote the manuscript; SLG, CF, DAD, AR, E-FG, P-JV and BB performed the experiments and analyzed the data; IH, ID-F and PM analyzed the data and reviewed the manu- script; BC designed the study and analyzed the data; MF designed the study, analyzed the data, supervised the work and wrote the manuscript.
Acknowledgments
The authors want to acknowledge Pr Olivier Kosmider, Dr Narla Mohandas, and Dr Christian Bastard for very helpful dis- cussions. They also want to thank Dr Franck Letourneur from the genom’IC platform, Florent Dumont, bioinformatician funded by the Site de Recherche Intégrée sur le Cancer (SIRIC) CAncer Research for PErsonalized Medicine CARPEM, Alice Rousseau for technical assistance and Marjorie Leduc from the 3P5 pro- teomic platform of Paris Descartes University.
Funding
This study was funded by INSERM, by the Institut National du Cancer (INCa) and the Direction Générale de l’Offre de Soins (DGOS) of the French Ministry of Social Affairs and Health through the Programme Hospitalier de Recherche Clinique (PHRC MDS-04: INCa-DGOS_5480). SLG was the recipient of a PhD funding from the Laboratory of Excellence on red cells GR-Ex.
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