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Predominance of spliceosomal complex formation over polyadenylation site selection in TDP-43 autoregulation.


ABSTRACT: 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.

SUBMITTER: Bembich S 

PROVIDER: S-EPMC3950720 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Predominance of spliceosomal complex formation over polyadenylation site selection in TDP-43 autoregulation.

Bembich Sara S   Herzog Jeremias S JS   De Conti Laura L   Stuani Cristiana C   Avendaño-Vázquez S Eréndira SE   Buratti Emanuele E   Baralle Marco M   Baralle Francisco E FE  

Nucleic acids research 20131224 5


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  ...[more]

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