CELF proteins regulate CFTR pre-mRNA splicing: essential role of the divergent domain of ETR-3
In: Nucleic Acids Research, Jg. 38 (2010-07-14), S. 7273-7285
Online
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Zugriff:
Cystic fibrosis is a prominent genetic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Among the many disease-causing alterations are pre-mRNA splicing defects that can hamper mandatory exon inclusion. CFTR exon 9 splicing depends in part on a polymorphic UG(m)U(n) sequence at the end of intron 8, which can be bound by TDP-43, leading to partial exon 9 skipping. CELF proteins, like CUG-BP1 and ETR-3, can also bind UG repeats and regulate splicing. We show here that ETR-3, but not CUG-BP1, strongly stimulates exon 9 skipping, although both proteins bind efficiently to the same RNA motif as TDP-43 and with higher affinity. We further show that the skipping of this exon may be due to the functional antagonism between U2AF65 and ETR-3 binding onto the polymorphic U or UG stretch, respectively. Importantly, we demonstrate that the divergent domain of ETR-3 is critical for CFTR exon 9 skipping, as shown by deletion and domain-swapping experiments. We propose a model whereby several RNA-binding events account for the complex regulation of CFTR exon 9 inclusion, with strikingly distinct activities of ETR-3 and CUG-BP1, related to the structure of their divergent domain.
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CELF proteins regulate CFTR pre-mRNA splicing: essential role of the divergent domain of ETR-3
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Autor/in / Beteiligte Person: | Buratti, Emanuele ; Catherine Le Jossic-Corcos ; Pagani, Franco ; Dujardin, Gwendal ; Mbopda, Annick ; Charlet-Berguerand, Nicolas ; Férec, Claude ; Corcos, Laurent ; Mafalda Martins de Araujo ; Génétique moléculaire et génétique épidémiologique ; Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM) ; International Centre for Genetic Engineering and Biotechnology (ICGEB) ; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA) |
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Zeitschrift: | Nucleic Acids Research, Jg. 38 (2010-07-14), S. 7273-7285 |
Veröffentlichung: | Oxford University Press (OUP), 2010 |
Medientyp: | unknown |
ISSN: | 1362-4962 (print) ; 0305-1048 (print) |
DOI: | 10.1093/nar/gkq573 |
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