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Frame-disrupting mutations elicit pre-mRNA accumulation independently of frame disruption
The T-cell receptor (TCR) and immunoglobulin (Ig) genes are unique among vertebrate genes in that they undergo programmed rearrangement, a process that allows them to generate an enormous array of receptors with different antigen specificities. While crucial for immune function, this rearrangement m...
Autores principales: | , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836556/ https://www.ncbi.nlm.nih.gov/pubmed/20007599 http://dx.doi.org/10.1093/nar/gkp1115 |
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author | Imam, J. Saadi Gudikote, Jayanthi P. Chan, Wai-kin Wilkinson, Miles F. |
author_facet | Imam, J. Saadi Gudikote, Jayanthi P. Chan, Wai-kin Wilkinson, Miles F. |
author_sort | Imam, J. Saadi |
collection | PubMed |
description | The T-cell receptor (TCR) and immunoglobulin (Ig) genes are unique among vertebrate genes in that they undergo programmed rearrangement, a process that allows them to generate an enormous array of receptors with different antigen specificities. While crucial for immune function, this rearrangement mechanism is highly error prone, often generating frameshift or nonsense mutations that render the rearranged TCR and Ig genes defective. Such frame-disrupting mutations have been reported to increase the level of TCRβ and Igµ pre-mRNA, suggesting the hypothesis that RNA processing is blocked when frame disruption is sensed. Using a chimeric gene that contains TCRβ sequences conferring this upregulatory response, we provide evidence that pre-mRNA upregulation is neither frame- nor translation-dependent; instead, several lines of evidence suggested that it is the result of disrupted cis elements necessary for efficient RNA splicing. In particular, we identify the rearranging VDJ(β) exon as being uniquely densely packed with exonic-splicing enhancers (ESEs), rendering this exon hypersensitive to mutational disruption. As the chimeric gene that we developed for these studies generates unusually stable nuclear pre-mRNAs that accumulate when challenged with ESE mutations, we suggest it can be used as a sensitive in vivo system to identify and characterize ESEs. |
format | Text |
id | pubmed-2836556 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-28365562010-03-11 Frame-disrupting mutations elicit pre-mRNA accumulation independently of frame disruption Imam, J. Saadi Gudikote, Jayanthi P. Chan, Wai-kin Wilkinson, Miles F. Nucleic Acids Res Molecular Biology The T-cell receptor (TCR) and immunoglobulin (Ig) genes are unique among vertebrate genes in that they undergo programmed rearrangement, a process that allows them to generate an enormous array of receptors with different antigen specificities. While crucial for immune function, this rearrangement mechanism is highly error prone, often generating frameshift or nonsense mutations that render the rearranged TCR and Ig genes defective. Such frame-disrupting mutations have been reported to increase the level of TCRβ and Igµ pre-mRNA, suggesting the hypothesis that RNA processing is blocked when frame disruption is sensed. Using a chimeric gene that contains TCRβ sequences conferring this upregulatory response, we provide evidence that pre-mRNA upregulation is neither frame- nor translation-dependent; instead, several lines of evidence suggested that it is the result of disrupted cis elements necessary for efficient RNA splicing. In particular, we identify the rearranging VDJ(β) exon as being uniquely densely packed with exonic-splicing enhancers (ESEs), rendering this exon hypersensitive to mutational disruption. As the chimeric gene that we developed for these studies generates unusually stable nuclear pre-mRNAs that accumulate when challenged with ESE mutations, we suggest it can be used as a sensitive in vivo system to identify and characterize ESEs. Oxford University Press 2010-03 2009-12-09 /pmc/articles/PMC2836556/ /pubmed/20007599 http://dx.doi.org/10.1093/nar/gkp1115 Text en © The Author(s) 2009. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/2.5 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Molecular Biology Imam, J. Saadi Gudikote, Jayanthi P. Chan, Wai-kin Wilkinson, Miles F. Frame-disrupting mutations elicit pre-mRNA accumulation independently of frame disruption |
title | Frame-disrupting mutations elicit pre-mRNA accumulation independently of frame disruption |
title_full | Frame-disrupting mutations elicit pre-mRNA accumulation independently of frame disruption |
title_fullStr | Frame-disrupting mutations elicit pre-mRNA accumulation independently of frame disruption |
title_full_unstemmed | Frame-disrupting mutations elicit pre-mRNA accumulation independently of frame disruption |
title_short | Frame-disrupting mutations elicit pre-mRNA accumulation independently of frame disruption |
title_sort | frame-disrupting mutations elicit pre-mrna accumulation independently of frame disruption |
topic | Molecular Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836556/ https://www.ncbi.nlm.nih.gov/pubmed/20007599 http://dx.doi.org/10.1093/nar/gkp1115 |
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