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Evolutionary Constraint Helps Unmask a Splicing Regulatory Region in BRCA1 Exon 11
BACKGROUND: Alternative splicing across exon 11 produces several BRCA1 isoforms. Their proportion varies during the cell cycle, between tissues and in cancer suggesting functional importance of BRCA1 splicing regulation around this exon. Although the regulatory elements driving exon 11 splicing have...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353946/ https://www.ncbi.nlm.nih.gov/pubmed/22615956 http://dx.doi.org/10.1371/journal.pone.0037255 |
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author | Raponi, Michela Douglas, Andrew G. L. Tammaro, Claudia Wilson, David I. Baralle, Diana |
author_facet | Raponi, Michela Douglas, Andrew G. L. Tammaro, Claudia Wilson, David I. Baralle, Diana |
author_sort | Raponi, Michela |
collection | PubMed |
description | BACKGROUND: Alternative splicing across exon 11 produces several BRCA1 isoforms. Their proportion varies during the cell cycle, between tissues and in cancer suggesting functional importance of BRCA1 splicing regulation around this exon. Although the regulatory elements driving exon 11 splicing have never been identified, a selective constraint against synonymous substitutions (silent nucleotide variations that do not alter the amino acid residue sequence) in a critical region of BRCA1 exon 11 has been reported to be associated with the necessity to maintain regulatory sequences. METHODOLOGY/PRINCIPAL FINDINGS: Here we have designed a specific minigene to investigate the possibility that this bias in synonymous codon usage reflects the need to preserve the BRCA1 alternative splicing program. We report that in-frame deletions and translationally silent nucleotide substitutions in the critical region affect splicing regulation of BRCA1 exon 11. CONCLUSIONS/SIGNIFICANCE: Using a hybrid minigene approach, we have experimentally validated the hypothesis that the need to maintain correct alternative splicing is a selective pressure against translationally silent sequence variations in the critical region of BRCA1 exon 11. Identification of the trans-acting factors involved in regulating exon 11 alternative splicing will be important in understanding BRCA1-associated tumorigenesis. |
format | Online Article Text |
id | pubmed-3353946 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33539462012-05-21 Evolutionary Constraint Helps Unmask a Splicing Regulatory Region in BRCA1 Exon 11 Raponi, Michela Douglas, Andrew G. L. Tammaro, Claudia Wilson, David I. Baralle, Diana PLoS One Research Article BACKGROUND: Alternative splicing across exon 11 produces several BRCA1 isoforms. Their proportion varies during the cell cycle, between tissues and in cancer suggesting functional importance of BRCA1 splicing regulation around this exon. Although the regulatory elements driving exon 11 splicing have never been identified, a selective constraint against synonymous substitutions (silent nucleotide variations that do not alter the amino acid residue sequence) in a critical region of BRCA1 exon 11 has been reported to be associated with the necessity to maintain regulatory sequences. METHODOLOGY/PRINCIPAL FINDINGS: Here we have designed a specific minigene to investigate the possibility that this bias in synonymous codon usage reflects the need to preserve the BRCA1 alternative splicing program. We report that in-frame deletions and translationally silent nucleotide substitutions in the critical region affect splicing regulation of BRCA1 exon 11. CONCLUSIONS/SIGNIFICANCE: Using a hybrid minigene approach, we have experimentally validated the hypothesis that the need to maintain correct alternative splicing is a selective pressure against translationally silent sequence variations in the critical region of BRCA1 exon 11. Identification of the trans-acting factors involved in regulating exon 11 alternative splicing will be important in understanding BRCA1-associated tumorigenesis. Public Library of Science 2012-05-16 /pmc/articles/PMC3353946/ /pubmed/22615956 http://dx.doi.org/10.1371/journal.pone.0037255 Text en Raponi et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Raponi, Michela Douglas, Andrew G. L. Tammaro, Claudia Wilson, David I. Baralle, Diana Evolutionary Constraint Helps Unmask a Splicing Regulatory Region in BRCA1 Exon 11 |
title | Evolutionary Constraint Helps Unmask a Splicing Regulatory Region in BRCA1 Exon 11 |
title_full | Evolutionary Constraint Helps Unmask a Splicing Regulatory Region in BRCA1 Exon 11 |
title_fullStr | Evolutionary Constraint Helps Unmask a Splicing Regulatory Region in BRCA1 Exon 11 |
title_full_unstemmed | Evolutionary Constraint Helps Unmask a Splicing Regulatory Region in BRCA1 Exon 11 |
title_short | Evolutionary Constraint Helps Unmask a Splicing Regulatory Region in BRCA1 Exon 11 |
title_sort | evolutionary constraint helps unmask a splicing regulatory region in brca1 exon 11 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353946/ https://www.ncbi.nlm.nih.gov/pubmed/22615956 http://dx.doi.org/10.1371/journal.pone.0037255 |
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