Stop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol response

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dc.contributor.authorLoughran, Gary
dc.contributor.authorJungreis, Irwin
dc.contributor.authorTzani, Ioanna
dc.contributor.authorPower, Michael
dc.contributor.authorDmitriev, Ruslan I.
dc.contributor.authorIvanov, Ivaylo P.
dc.contributor.authorKellis, Manolis
dc.contributor.authorAtkins, John F.
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderNational Institutes of Healthen
dc.contributor.funderWellcome Trusten
dc.contributor.funderHealth Research Boarden
dc.date.accessioned2018-03-28T15:55:34Z
dc.date.available2018-03-28T15:55:34Z
dc.date.issued2018-01-31
dc.date.updated2018-03-28T15:43:20Z
dc.description.abstractAlthough stop codon readthrough is used extensively by viruses to expand their gene expression, verified instances of mammalian readthrough have only recently been uncovered by systems biology and comparative genomics approaches. Previously our analysis of conserved protein coding signatures that extend beyond annotated stop codons predicted stop codon readthrough of several mammalian genes, all of which have been validated experimentally. Four mRNAs display highly efficient stop codon readthrough, and these mRNAs have a UGA stop codon immediately followed by CUAG (UGA_CUAG) that is conserved throughout vertebrates. Extending on the identification of this readthrough motif, we here investigated stop codon readthrough, using tissue culture reporter assays, for all previously untested human genes containing UGA_CUAG. The readthrough efficiency of the annotated stop codon for the sequence encoding vitamin D receptor (VDR) was 6.7%. It was the highest of those tested but all showed notable levels of readthrough. The VDR is a member of the nuclear receptor superfamily of ligand-inducible transcription factors and binds its major ligand, calcitriol, via its C-terminal ligand-binding domain. Readthrough of the annotated VDR mRNA results in a 67 amino-acid-long C-terminal extension that generates a VDR proteoform named VDRx. VDRx may form homodimers and heterodimers with VDR but, compared to VDR, VDRx displayed a reduced transcriptional response to calcitriol even in the presence of its partner retinoid X receptor.en
dc.description.sponsorshipHealth Research Board (Award (PhD/2007/04))en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationLoughran, G., Jungreis, I., Tzani, I., Power, M., Dmitriev, R. I., Ivanov, I. P., Kellis, M. and Atkins, J. F. (2018) 'Stop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol response', Journal of Biological Chemistry, 293 (12), pp. 4434-4444. doi:10.1074/jbc.M117.818526en
dc.identifier.doi10.1074/jbc.M117.818526
dc.identifier.endpage4444en
dc.identifier.issn1083-351X
dc.identifier.issn0021-9258
dc.identifier.issued12en
dc.identifier.journaltitleJournal of Biological Chemistryen
dc.identifier.startpage4434en
dc.identifier.urihttps://hdl.handle.net/10468/5716
dc.identifier.volume293en
dc.language.isoenen
dc.publisherThe American Society for Biochemistry and Molecular Biology, Inc.en
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Investigator Programme/12/IP/1492/IE/Using ribosome profiling to study translation initiation/elongation and facilitate optimization of protein synthesis/en
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Starting Investigator Research Grant (SIRG)/13/SIRG/2144/IE/Development of Bionic Sensor Materials for Metabolic Imaging in Regenerative Medicine/en
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Investigator Programme/13/IA/1853/IE/Dynamic redefinition of codons: From antivirals to an essential micronutrient/en
dc.relation.projectinfo:eu-repo/grantAgreement/NIH/NATIONAL HUMAN GENOME RESEARCH INSTITUTE/1R01HG004037-01A1/US/Regulatory Morif Discovery in the Human Genome Using Comparative Genomics/en
dc.relation.projectinfo:eu-repo/grantAgreement/NIH/NATIONAL HUMAN GENOME RESEARCH INSTITUTE/1U41HG007234-01/US/GENCODE: comprehensive gene annotation for human and mouse/en
dc.relation.urihttp://www.jbc.org/content/293/12/4434.full
dc.rights© 2018 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version free via Creative Commons CC-BY license.en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectNuclear receptoren
dc.subjectTranscription factoren
dc.subjecttransfer RNA (tRNA)en
dc.subjectTranslation release factoren
dc.subjectVitamin Den
dc.subjectVDRen
dc.subjectCalcitriolen
dc.subjectPhyloCSFen
dc.subjectReadthroughen
dc.subjectStop codonen
dc.titleStop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol responseen
dc.typeArticle (peer-reviewed)en
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