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J. Biol. Chem., Vol. 278, Issue 52, 52166-52171, December 26, 2003

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Influence of Polymerase II Processivity on Alternative Splicing Depends on Splice Site Strength^*

Guadalupe Nogués, Manuel J. Muñoz, and Alberto R. Kornblihtt, Howard Hughes Medical Institute International Research Scholar and a career investigator of the Consejo Nacional de Investigaciones Científicas y Técnicas.¶

From the Laboratorio de Fisiología y Biología Molecular, Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and IFIBYNE-CONICET, Ciudad Universitaria, Pabellón II (C1428EHA), Buenos Aires, Argentina

Transcription and pre-mRNA splicing are coordinated temporally and spatially, and both processes can influence each other. In particular, control of transcriptional elongation by RNA polymerase II has proved to be important for alternative splicing regulation. In this report we demonstrate that the efficiency of exon recognition by the splicing machinery is crucial for the elongation control. Alternative splicing of the fibronectin extra domain I (EDI) is because the polypyrimidine tract of its 3'-splice site occurs suboptimal. By mutating the polypyrimidine tract of EDI in two different positions, individually or in combination, and by disrupting its exonic splicing silencer, we managed to generate minigenes with increasing degrees of exon recognition. Improvement of exon recognition is evidenced by independence from the splicing regulator SF2/ASF for inclusion. The mutated minigenes were used to transfect human cells in culture and study the responsiveness of EDI alternative splicing to activation or inhibition of pol II elongation. Our results revealed that responsiveness of exon skipping to elongation is inversely proportional to 3'-splice site strength, which means that the better the alternative exon is recognized by the splicing machinery, the less its degree of inclusion is affected by transcriptional elongation.

Received for publication, August 18, 2003

^* This work was supported in part by grants from the Fundación Antorchas, the International Centre for Genetic Engineering and Biotechnology, and the Agencia Nacional de Promoción de Ciencia y Tecnología of Argentina (ANPCYT). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a fellowship from the Consejo Nacional de Investigaciones Científicas y Técnicas of Argentina.

Recipient of a fellowship from the ANPCYT.

^¶ To whom correspondence should be addressed. Tel.: 54-11-4576-3386; Fax: 54-11-4576-3321; E-mail: ark{at}fbmc.fcen.uba.ar.

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