Evolutionarily conserved inhibitory uORFs sensitize Hox mRNA translation to start codon selection stringency.
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Authors
Wang, Ji
Firth, Andrew E
Cao, Chune
Dever, Thomas E
Publication Date
2022-03-01Journal Title
Proc Natl Acad Sci U S A
ISSN
0027-8424
Publisher
Proceedings of the National Academy of Sciences
Volume
119
Issue
9
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Ivanov, I. P., Saba, J. A., Fan, C., Wang, J., Firth, A. E., Cao, C., Green, R., & et al. (2022). Evolutionarily conserved inhibitory uORFs sensitize Hox mRNA translation to start codon selection stringency.. Proc Natl Acad Sci U S A, 119 (9) https://doi.org/10.1073/pnas.2117226119
Abstract
Translation start site selection in eukaryotes is influenced by context nucleotides flanking the AUG codon and by levels of the eukaryotic translation initiation factors eIF1 and eIF5. In a search of mammalian genes, we identified five homeobox (Hox) gene paralogs initiated by AUG codons in conserved suboptimal context as well as 13 Hox genes that contain evolutionarily conserved upstream open reading frames (uORFs) that initiate at AUG codons in poor sequence context. An analysis of published cap analysis of gene expression sequencing (CAGE-seq) data and generated CAGE-seq data for messenger RNAs (mRNAs) from mouse somites revealed that the 5' leaders of Hox mRNAs of interest contain conserved uORFs, are generally much shorter than reported, and lack previously proposed internal ribosome entry site elements. We show that the conserved uORFs inhibit Hox reporter expression and that altering the stringency of start codon selection by overexpressing eIF1 or eIF5 modulates the expression of Hox reporters. We also show that modifying ribosome homeostasis by depleting a large ribosomal subunit protein or treating cells with sublethal concentrations of puromycin leads to lower stringency of start codon selection. Thus, altering global translation can confer gene-specific effects through altered start codon selection stringency.
Keywords
Hox genes, uORF, Eif1, Eif5, Start Codon Selection Stringency, Animals, Mice, RNA, Messenger, Codon, Initiator, Evolution, Molecular, Protein Biosynthesis, Genes, Homeobox, Open Reading Frames
Sponsorship
HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR071976, AR060042, AR072644)
NCI NIH HHS (F30 CA260910)
NIAMS NIH HHS (R01 AR071976, R01 AR060042, R01 AR072644)
Wellcome Trust (220814)
Howard Hughes Medical Institute (00)
HHS | NIH | National Cancer Institute (F30CA260910)
HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (ZIA HD01010)
Identifiers
35217614, PMC8892498
External DOI: https://doi.org/10.1073/pnas.2117226119
This record's URL: https://www.repository.cam.ac.uk/handle/1810/335496
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/
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