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J Biol Chem. 2018 Mar 23;293(12):4434-4444. doi: 10.1074/jbc.M117.818526. Epub 2018 Jan 31.

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

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From the School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland,
Computer Science and Artificial Intelligence Laboratory (CSAIL), Massachusetts Institute of Technology, Cambridge, Massachusetts 02139-4307, and.
From the School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.
From the School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland,
Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112-5330.


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 it 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 with VDR, VDRx displayed a reduced transcriptional response to calcitriol even in the presence of its partner retinoid X receptor.


PhyloCSF; VDR; calcitriol; nuclear receptor; readthrough; stop codon; transcription factor; transfer RNA (tRNA); translation release factor; vitamin D

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