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J. Biol. Chem., Vol. 277, Issue 45, 43110-43114, November 8, 2002
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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, Ciudad Universitaria,
Pabellón II, C1428EHA Buenos Aires, Argentina and the
Promoter and enhancer elements can influence
alternative splicing, but the basis for this phenomenon is not well
understood. Here we investigated how different transcriptional
activators affect the decision between inclusion and exclusion
(skipping) of the fibronectin EDI exon. A mutant of the acidic VP16
activation domain called SW6 that preferentially inhibits polymerase II
(pol II) elongation caused a reduction in EDI exon skipping. Exon
skipping was fully restored in the presence of the SW6 mutant by either the SV40 enhancer in cis or the human immunodeficiency virus (HIV) Tat
in trans, both of which specifically stimulate pol II elongation. HIV
Tat also cooperated with the Sp1 and CTF activation domains to
enhance transcript elongation and EDI skipping. The extent of exon
skipping correlated with the efficiency with which pol II transcripts
reach the 3' end of the gene but not with the overall fold increase in
transcript levels caused by different activators. The ability of
activators to enhance elongation by RNA polymerase II therefore
correlates with their ability to enhance exon skipping. Consistent with
this observation, the elongation inhibitor
dichlororibofuranosylbenzimidazole (DRB) enhanced EDI inclusion.
Conversely, the histone deacetylase inhibitor trichostatin A that is
thought to stimulate elongation caused a modest inhibition of EDI
inclusion. Together our results support a kinetic coupling model in
which the rate of transcript elongation determines the outcome of two
competing splicing reactions that occur co-transcriptionally. Rapid,
highly processive transcription favors EDI exon skipping, whereas
slower, less processive transcription favors inclusion.
Transcriptional Activators Differ in Their Abilities to Control
Alternative Splicing*
,
**, and
Department of Biochemistry and Molecular Genetics,
University of Colorado Health Sciences Center, Denver, Colorado
80262
*
This work was supported 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 (to A. R. K.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The 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 (CONICET) of Argentina.
§
Recipient of a fellowship from the University of Buenos Aires.
¶
Present address: Dept. of Molecular and Cellular Biology,
Harvard University, 7 Divinity Ave., Cambridge, MA 02138.
**
Supported by National Institutes of Health Grant GM58613.
Howard Hughes Medical Institute International Research Scholar
and a career investigator of the CONICET. To whom correspondence should
be addressed. Tel.: 54-11-4576-3386; Fax: 54-11-4576-3321; E-mail:
ark@fbmc.fcen.uba.ar.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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