Stop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol response
© 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 approa...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier BV
2022
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| Online Access: | https://hdl.handle.net/1721.1/134162.2 |
| _version_ | 1811091941673140224 |
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| author | Loughran, Gary Jungreis, Irwin Tzani, Ioanna Power, Michael Dmitriev, Ruslan I Ivanov, Ivaylo P Kellis, Manolis Atkins, John F |
| author2 | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory |
| author_facet | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Loughran, Gary Jungreis, Irwin Tzani, Ioanna Power, Michael Dmitriev, Ruslan I Ivanov, Ivaylo P Kellis, Manolis Atkins, John F |
| author_sort | Loughran, Gary |
| collection | MIT |
| description | © 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. |
| first_indexed | 2024-09-23T15:10:23Z |
| format | Article |
| id | mit-1721.1/134162.2 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T15:10:23Z |
| publishDate | 2022 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/134162.22022-07-11T16:05:02Z 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 Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science © 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. 2022-07-11T16:05:00Z 2021-10-27T19:58:26Z 2022-07-11T16:05:00Z 2018 2019-06-07T15:02:13Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/134162.2 en 10.1074/JBC.M117.818526 Journal of Biological Chemistry Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/octet-stream Elsevier BV American Society for Biochemistry and Molecular Biology |
| spellingShingle | Loughran, Gary Jungreis, Irwin Tzani, Ioanna Power, Michael Dmitriev, Ruslan I Ivanov, Ivaylo P Kellis, Manolis Atkins, John F Stop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol response |
| title | Stop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol response |
| title_full | Stop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol response |
| title_fullStr | Stop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol response |
| title_full_unstemmed | Stop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol response |
| title_short | Stop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol response |
| title_sort | stop codon readthrough generates a c terminally extended variant of the human vitamin d receptor with reduced calcitriol response |
| url | https://hdl.handle.net/1721.1/134162.2 |
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