Published online 19 March 2004
Nucleic Acids Research, 2004, Vol. 32, No. 5 1783-1791
Oxford University Press
Silencer elements as possible inhibitors of pseudoexon splicing
1 IRCCS E. Medea, Associazione La Nostra Famiglia, 23842 Bosisio Parini (LC), 2 Department of Biomedical Engineering, Polytechnic University, Milan, Italy and 3 Centro Dino Ferrari, Dipartimento di Scienze Neurologiche, Università di Milano, IRCCS Ospedale Maggiore Policlinico, 20100 Milan, Italy
*To whom correspondence should be addressed. Tel: +39 031 877111; Fax: +39 031 877499; Email: msironi{at}bp.lnf.it
Received December 18, 2003; Revised February 11, 2004; Accepted February 24, 2004
Human pre-mRNAs contain a definite number of exons and several pseudoexons which are located within intronic regions. We applied a computational approach to address the question of how pseudoexons are neglected in favor of exons and to possibly identify sequence elements preventing pseudoexon splicing. A search for possible splicing silencers was carried out on a pseudoexon selection that resembled exons in terms of splice site strength and exon splicing enhancer (ESE) representation; three motifs were retrieved through hexamer composition comparisons. One of these functions as a powerful silencer in transfection-based splicing assays and matches a previously identified silencer sequence with hnRNP H binding ability. The other two motifs are novel and failed to induce skipping of a constitutive exon, indicating that they might act as weak repressors or in synergy with other unidentified elements. All three motifs are enriched in pseudoexons compared with intronic regions and display higher frequencies in intronless gene-coding sequences compared with exons. We consider that a subpopulation of pseudoexons might rely on negative regulators for splicing repression; this hypothesis, if experimentally verified, might improve our understanding of exonic splicing regulatory sequences and provide the identification of a novel mutation target for human genetic diseases.
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