TDP43 depletion rescues aberrant CFTR exon 9 skipping

被引：69

作者：

Ayala, YM ^{[1
]}

Pagani, F ^{[1
]}

Baralle, FE ^{[1
]}

机构：

[1] Int Ctr Genet Engn & Biotechnol, Dept Mol Pathol, I-34012 Trieste, Italy

来源：

FEBS LETTERS | 2006年 / 580卷 / 05期

关键词：

TDP43; alternative splicing; hnRNP; CFTR exon 9; cystic fibrosis; splicing regulation;

D O I：

10.1016/j.febslet.2006.01.052

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

CFTR exon 9 presents a 3' splice site polymorphism, (UG)(m)U-n, whose composition influences splicing. TDP43 specifically binds the UG tract of the transcript and inhibits splicing in vitro. We report that depletion of TDP43 through RNA interference removes splicing inhibition caused by unfavorable (UG)(m)U-n sequences, indicating that TDP43 exerts a potent inhibitory effect in vivo. We also show that the UG-TDP43 interaction has a dominant role over other exon 9 splicing regulatory elements. These results suggest that TDP43 association near a splice site has determined the evolution of positive splicing regulatory elements to contrast this inhibition. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

引用

页码：1339 / 1344

页数：6

共 19 条

[1] Human, Drosophila, and C-elegans TDP43:: Nucleic acid binding properties and splicing regulatory function [J].

Ayala, YM ;

Pantano, S ;

D'Ambrogio, A ;

Buratti, E ;

Brindisi, A ;

Marchetti, C ;

Romano, M ;

Baralle, FE .

JOURNAL OF MOLECULAR BIOLOGY, 2005, 348 (03) :575-588

[2] Nuclear factor TDP-43 binds to the polymorphic TG repeats in CFTR intron 8 and causes skipping of Exon 9: A functional link with disease penetrance [J].

Buratti, E ;

Brindisi, A ;

Pagani, F ;

Baralle, FE .

AMERICAN JOURNAL OF HUMAN GENETICS, 2004, 74 (06) :1322-1325

[3] Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9 [J].

Buratti, E ;

Baralle, FE .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (39) :36337-36343

[4] Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping [J].

Buratti, E ;

Dörk, T ;

Zuccato, E ;

Pagani, F ;

Romano, M ;

Baralle, FE .

EMBO JOURNAL, 2001, 20 (07) :1774-1784

[5]

BURGE CB, 1999, RNA WORLD

[6] VARIABLE DELETION OF EXON-9 CODING SEQUENCES IN CYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR GENE MESSENGER-RNA TRANSCRIPTS IN NORMAL BRONCHIAL EPITHELIUM [J].

CHU, CS ;

TRAPNELL, BC ;

MURTAGH, JJ ;

MOSS, J ;

DALEMANS, W ;

JALLAT, S ;

MERCENIER, A ;

PAVIRANI, A ;

LECOCQ, JP ;

CUTTING, GR ;

GUGGINO, WB ;

CRYSTAL, RG .

EMBO JOURNAL, 1991, 10 (06) :1355-1363

[7] Polyvariant mutant cystic fibrosis transmembrane conductance regulator genes - The polymorphic (TG)m locus explains the partial penetrance of the T5 polymorphism as a disease mutation [J].

Cuppens, H ;

Lin, W ;

Jaspers, M ;

Costes, B ;

Teng, H ;

Vankeerberghen, A ;

Jorissen, M ;

Droogmans, G ;

Reynaert, I ;

Goossens, M ;

Nilius, B ;

Cassiman, JJ .

JOURNAL OF CLINICAL INVESTIGATION, 1998, 101 (02) :487-496

[8] A variable dinucleotide repeat in the CFTR gene contributes to phenotype diversity by forming RNA secondary structures that alter splicing [J].

Hefferon, TW ;

Groman, JD ;

Yurk, CE ;

Cutting, GR .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (10) :3504-3509

[9] IDENTIFICATION OF THE CYSTIC-FIBROSIS GENE - GENETIC-ANALYSIS [J].

KEREM, BS ;

ROMMENS, JM ;

BUCHANAN, JA ;

MARKIEWICZ, D ;

COX, TK ;

CHAKRAVARTI, A ;

BUCHWALD, M ;

TSUI, LC .

SCIENCE, 1989, 245 (4922) :1073-1080

[10] Small interfering RNA-mediated gene silencing in T lymphocytes [J].

McManus, MT ;

Haines, BB ;

Dillon, CP ;

Whitehurst, CE ;

van Parijs, L ;

Chen, JZ ;

Sharp, PA .

JOURNAL OF IMMUNOLOGY, 2002, 169 (10) :5754-5760

← 1 2 →