Stop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol response
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.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.date.accessioned | 2018-03-28T15:55:34Z | |
dc.date.available | 2018-03-28T15:55:34Z | |
dc.date.issued | 2018-01-31 | |
dc.date.updated | 2018-03-28T15:43:20Z | |
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.description.status | Peer reviewed | en |
dc.description.version | Published Version | en |
dc.format.mimetype | application/pdf | en |
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.doi | 10.1074/jbc.M117.818526 | |
dc.identifier.endpage | 4444 | en |
dc.identifier.issn | 1083-351X | |
dc.identifier.issn | 0021-9258 | |
dc.identifier.issued | 12 | en |
dc.identifier.journaltitle | Journal of Biological Chemistry | en |
dc.identifier.startpage | 4434 | en |
dc.identifier.uri | https://hdl.handle.net/10468/5716 | |
dc.identifier.volume | 293 | en |
dc.language.iso | en | en |
dc.publisher | The American Society for Biochemistry and Molecular Biology, Inc. | 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 |
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 |