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Stop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol response
Loughran, Gary; Jungreis, Irwin; Tzani, Ioanna; Power, Michael; Dmitriev, Ruslan I.; Ivanov, Ivaylo P.; Kellis, Manolis; Atkins, John F.
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.
Keyword(s): Nuclear receptor; Transcription factor; transfer RNA (tRNA); Translation release factor; Vitamin D; VDR; Calcitriol; PhyloCSF; Readthrough; Stop codon
Publication Date:
Type: Journal article
Peer-Reviewed: Yes
Language(s): English
Institution: University College Cork
Funder(s): Science Foundation Ireland; Health Research Board
Citation(s): 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
Publisher(s): The American Society for Biochemistry and Molecular Biology, Inc.
File Format(s): application/pdf
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First Indexed: 2018-03-29 06:30:11 Last Updated: 2018-03-29 06:30:11