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Predominance of spliceosomal complex formation over polyadenylation site selection in TDP-43 autoregulation
TDP-43 is a nuclear protein involved in many aspects of RNA metabolism. To ensure cellular viability, its expression levels within cells must be tightly regulated. We have previously demonstrated that TDP-43 autoregulation occurs through the activation of a normally silent intron in its 3′-UTR seque...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2014
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3950720/ https://www.ncbi.nlm.nih.gov/pubmed/24369426 http://dx.doi.org/10.1093/nar/gkt1343 |
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author | Bembich, Sara Herzog, Jeremias S. De Conti, Laura Stuani, Cristiana Avendaño-Vázquez, S. Eréndira Buratti, Emanuele Baralle, Marco Baralle, Francisco E. |
author_facet | Bembich, Sara Herzog, Jeremias S. De Conti, Laura Stuani, Cristiana Avendaño-Vázquez, S. Eréndira Buratti, Emanuele Baralle, Marco Baralle, Francisco E. |
author_sort | Bembich, Sara |
collection | PubMed |
description | TDP-43 is a nuclear protein involved in many aspects of RNA metabolism. To ensure cellular viability, its expression levels within cells must be tightly regulated. We have previously demonstrated that TDP-43 autoregulation occurs through the activation of a normally silent intron in its 3′-UTR sequence that results in the use of alternative polyadenylation sites. In this work, we analyse which is the dominant event in autoregulation: the recognition of the splice sites of 3′-UTR intron 7 or the intrinsic quality of the alternative polyadenylation sites. A panel of minigene constructs was tested for autoregulation functionality, protein production and subcellular messenger RNA localization. Our data clearly indicate that constitutive spliceosome complex formation across intron 7 does not lead to high protein production but, on the contrary, to lower TDP-43 messenger RNA and protein levels. This is due to altered nucleocytoplasmic distribution of the RNA that is mostly retained in the nucleus and degraded. This study provides a novel in-depth characterization of how RNA binding proteins can autoregulate their own levels within cells, an essential regulatory process in maintaining cellular viability. |
format | Online Article Text |
id | pubmed-3950720 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-39507202014-03-12 Predominance of spliceosomal complex formation over polyadenylation site selection in TDP-43 autoregulation Bembich, Sara Herzog, Jeremias S. De Conti, Laura Stuani, Cristiana Avendaño-Vázquez, S. Eréndira Buratti, Emanuele Baralle, Marco Baralle, Francisco E. Nucleic Acids Res TDP-43 is a nuclear protein involved in many aspects of RNA metabolism. To ensure cellular viability, its expression levels within cells must be tightly regulated. We have previously demonstrated that TDP-43 autoregulation occurs through the activation of a normally silent intron in its 3′-UTR sequence that results in the use of alternative polyadenylation sites. In this work, we analyse which is the dominant event in autoregulation: the recognition of the splice sites of 3′-UTR intron 7 or the intrinsic quality of the alternative polyadenylation sites. A panel of minigene constructs was tested for autoregulation functionality, protein production and subcellular messenger RNA localization. Our data clearly indicate that constitutive spliceosome complex formation across intron 7 does not lead to high protein production but, on the contrary, to lower TDP-43 messenger RNA and protein levels. This is due to altered nucleocytoplasmic distribution of the RNA that is mostly retained in the nucleus and degraded. This study provides a novel in-depth characterization of how RNA binding proteins can autoregulate their own levels within cells, an essential regulatory process in maintaining cellular viability. Oxford University Press 2014-03 2013-12-24 /pmc/articles/PMC3950720/ /pubmed/24369426 http://dx.doi.org/10.1093/nar/gkt1343 Text en © The Author(s) 2013. Published by Oxford University Press. http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Bembich, Sara Herzog, Jeremias S. De Conti, Laura Stuani, Cristiana Avendaño-Vázquez, S. Eréndira Buratti, Emanuele Baralle, Marco Baralle, Francisco E. Predominance of spliceosomal complex formation over polyadenylation site selection in TDP-43 autoregulation |
title | Predominance of spliceosomal complex formation over polyadenylation site selection in TDP-43 autoregulation |
title_full | Predominance of spliceosomal complex formation over polyadenylation site selection in TDP-43 autoregulation |
title_fullStr | Predominance of spliceosomal complex formation over polyadenylation site selection in TDP-43 autoregulation |
title_full_unstemmed | Predominance of spliceosomal complex formation over polyadenylation site selection in TDP-43 autoregulation |
title_short | Predominance of spliceosomal complex formation over polyadenylation site selection in TDP-43 autoregulation |
title_sort | predominance of spliceosomal complex formation over polyadenylation site selection in tdp-43 autoregulation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3950720/ https://www.ncbi.nlm.nih.gov/pubmed/24369426 http://dx.doi.org/10.1093/nar/gkt1343 |
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