CELF proteins regulate CFTR pre-mRNA splicing: essential role of the divergent domain of ETR-3.

Nucleic Acids Research
Gwendal DujardinLaurent Corcos

Abstract

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.

References

Jun 1, 1995·The New England Journal of Medicine·M ChillónM Claustres
Jun 2, 1997·The Journal of Cell Biology·M Gama-CarvalhoM Carmo-Fonseca
Sep 1, 1996·Molecular Human Reproduction·M De Braekeleer, C Férec
Apr 5, 2002·Molecular Cell·Nicolas Charlet-BThomas A Cooper
Feb 20, 2004·Nucleic Acids Research·Gopal SinghThomas A Cooper
Feb 12, 2005·Reproductive Biomedicine Online·Mireille Claustres
Feb 7, 2006·FEBS Letters·Youhna M AyalaFrancisco E Baralle
Jul 1, 2006·Science·Luis Miguel Mendes SoaresJuan Valcárcel
Feb 9, 2008·American Journal of Physiology. Gastrointestinal and Liver Physiology·Satish RamalingamShrikant Anant
May 12, 2009·Nucleic Acids Research·Andrea D'AmbrogioFrancisco E Baralle
Jun 26, 2009·Nucleic Acids Research·Kengo TsudaShigeyuki Yokoyama

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Citations

Feb 7, 2013·Nature Reviews. Molecular Cell Biology·Alberto R KornblihttManuel J Muñoz
Dec 20, 2011·Wiley Interdisciplinary Reviews. RNA·Twishasri Dasgupta, Andrea N Ladd
Nov 22, 2011·Journal of Molecular Biology·Monica PassoniEmanuele Buratti
Jan 19, 2013·Biochimica Et Biophysica Acta·Irina Vlasova-St LouisCarol J Wilusz
Feb 15, 2011·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Gwendal DujardinLaurent Corcos
Jun 4, 2015·Annual Review of Biochemistry·Shiran NaftelbergAlberto R Kornblihtt
May 6, 2014·Molecular Cell·Gwendal DujardinAlberto R Kornblihtt
Jun 12, 2013·Nucleic Acids Research·John M EdwardsMark S Searle
Nov 4, 2015·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Angela Schulz, Burkhard Tümmler
Jul 18, 2016·Colloids and Surfaces. B, Biointerfaces·W AndrzejewskaM Kozak
Sep 25, 2017·Nature Communications·Nana Diarra Dit KontéFrédéric H-T Allain
Jan 27, 2020·Journal of Clinical Immunology·Pavla HujováTomáš Freiberger
Dec 3, 2014·Genes & Development·Nova FongDavid L Bentley

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Methods Mentioned

BETA
exponential enrichment
transfection
electrophoresis
PCR
Assay
co-IP
in vitro transcription
co-immunoprecipitation

Software Mentioned

Rad Chemidoc XR
Bio
Gel Doc

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