Stop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol response
Name
J. Biol. Chem.-2018-Loughran-4434-44.pdf
Description
Published version
Size
4.16 MB
Format
Unknown
Checksum (MD5)
82648bc2f2d5df4e2bde6b9d233fd3a2
Author(s)
Loughran, Gary
Jungreis, Irwin
Tzani, Ioanna
Power, Michael
Dmitriev, Ruslan I
Ivanov, Ivaylo P
Kellis, Manolis
Atkins, John F
Date Issued
2018
Journal
Journal of Biological Chemistry
Publisher
Elsevier BV
Version
Final published version
Abstract
© 2018 by The American Society for Biochemistry and Molecular Biology, Inc. 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.
MIT Department
Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1074/JBC.M117.818526
