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.author Loughran, Gary
dc.contributor.author Jungreis, Irwin
dc.contributor.author Tzani, Ioanna
dc.contributor.author Power, Michael
dc.contributor.author Dmitriev, Ruslan I.
dc.contributor.author Ivanov, Ivaylo P.
dc.contributor.author Kellis, Manolis
dc.contributor.author Atkins, John F.
dc.date.accessioned 2018-03-28T15:55:34Z
dc.date.available 2018-03-28T15:55:34Z
dc.date.issued 2018-01-31
dc.identifier.citation Loughran, 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.M117.818526 en
dc.identifier.volume 293 en
dc.identifier.issued 12 en
dc.identifier.startpage 4434 en
dc.identifier.endpage 4444 en
dc.identifier.issn 1083-351X
dc.identifier.issn 0021-9258
dc.identifier.uri http://hdl.handle.net/10468/5716
dc.identifier.doi 10.1074/jbc.M117.818526
dc.description.abstract Although 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.sponsorship Health Research Board (Award (PhD/2007/04)) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher The American Society for Biochemistry and Molecular Biology, Inc. en
dc.relation.uri http://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.uri https://creativecommons.org/licenses/by/4.0/ en
dc.subject Nuclear receptor en
dc.subject Transcription factor en
dc.subject transfer RNA (tRNA) en
dc.subject Translation release factor en
dc.subject Vitamin D en
dc.subject VDR en
dc.subject Calcitriol en
dc.subject PhyloCSF en
dc.subject Readthrough en
dc.subject Stop codon en
dc.title Stop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol response en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother John F. Atkins, Biochemistry, University College Cork, Cork, Ireland. +353-21-490-3000 Email: j.atkins@ucc.ie en
dc.internal.availability Full text available en
dc.date.updated 2018-03-28T15:43:20Z
dc.description.version Published Version en
dc.internal.rssid 431673420
dc.contributor.funder Science Foundation Ireland en
dc.contributor.funder National Institutes of Health en
dc.contributor.funder Wellcome Trust en
dc.contributor.funder Health Research Board en
dc.description.status Peer reviewed en
dc.identifier.journaltitle Journal of Biological Chemistry en
dc.internal.copyrightchecked No !!CORA!! en
dc.internal.licenseacceptance Yes en
dc.internal.IRISemailaddress j.atkins@ucc.ie en
dc.internal.IRISemailaddress r.dmitriev@ucc.ie en
dc.relation.project info: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.project info: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.project info:eu-repo/grantAgreement/SFI/SFI Investigator Programme/13/IA/1853/IE/Dynamic redefinition of codons: From antivirals to an essential micronutrient/ en
dc.relation.project info: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.project info:eu-repo/grantAgreement/NIH/NATIONAL HUMAN GENOME RESEARCH INSTITUTE/1U41HG007234-01/US/GENCODE: comprehensive gene annotation for human and mouse/ en


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© 2018 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version free via Creative Commons CC-BY license. Except where otherwise noted, this item's license is described as © 2018 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version free via Creative Commons CC-BY license.
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