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dc.contributor.authorIvanov, Ivaylo P
dc.contributor.authorSaba, James A
dc.contributor.authorFan, Chen-Ming
dc.contributor.authorWang, Ji
dc.contributor.authorFirth, Andrew E
dc.contributor.authorCao, Chune
dc.contributor.authorGreen, Rachel
dc.contributor.authorDever, Thomas E
dc.date.accessioned2022-03-30T01:01:56Z
dc.date.available2022-03-30T01:01:56Z
dc.date.issued2022-03-01
dc.identifier.issn0027-8424
dc.identifier.other35217614
dc.identifier.otherPMC8892498
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/335496
dc.description.abstractTranslation 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.
dc.languageeng
dc.publisherProceedings of the National Academy of Sciences
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourceessn: 1091-6490
dc.sourcenlmid: 7505876
dc.subjectHox genes
dc.subjectuORF
dc.subjectEif1
dc.subjectEif5
dc.subjectStart Codon Selection Stringency
dc.subjectAnimals
dc.subjectMice
dc.subjectRNA, Messenger
dc.subjectCodon, Initiator
dc.subjectEvolution, Molecular
dc.subjectProtein Biosynthesis
dc.subjectGenes, Homeobox
dc.subjectOpen Reading Frames
dc.titleEvolutionarily conserved inhibitory uORFs sensitize Hox mRNA translation to start codon selection stringency.
dc.typeArticle
dc.date.updated2022-03-30T01:01:54Z
prism.issueIdentifier9
prism.publicationNameProc Natl Acad Sci U S A
prism.volume119
dc.identifier.doi10.17863/CAM.82927
dcterms.dateAccepted2022-01-20
rioxxterms.versionofrecord10.1073/pnas.2117226119
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.contributor.orcidIvanov, Ivaylo P [0000-0002-6008-3261]
dc.contributor.orcidSaba, James A [0000-0003-3453-8151]
dc.contributor.orcidFan, Chen-Ming [0000-0003-3211-6617]
dc.contributor.orcidGreen, Rachel [0000-0001-9337-2003]
dc.identifier.eissn1091-6490
pubs.funder-project-idHHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR071976, AR060042, AR072644)
pubs.funder-project-idNCI NIH HHS (F30 CA260910)
pubs.funder-project-idNIAMS NIH HHS (R01 AR071976, R01 AR060042, R01 AR072644)
pubs.funder-project-idWellcome Trust (220814)
pubs.funder-project-idHoward Hughes Medical Institute (00)
pubs.funder-project-idHHS | NIH | National Cancer Institute (F30CA260910)
pubs.funder-project-idHHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (ZIA HD01010)
cam.issuedOnline2022-02-25


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Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's licence is described as Attribution-NonCommercial-NoDerivatives 4.0 International