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Altered Serine/Arginine-Rich Protein Phosphorylation and Exonic Enhancer-Dependent Splicing in Mammalian Cells Lacking Topoisomerase I

¹ Institut de Génétique Moléculaire, Centre National de la Recherche Scientifique/UMR5535, and Institut Fédératif de Recherches 122 Montpellier, France;
² Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland; and
³ Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, C. U. de Strasbourg, France

DNA topoisomerase I (Topo I) specifically phosphorylates arginine-serine-rich (SR proteins) splicing factors and is potentially involved in pre-mRNA-splicing regulation. Using a Topo I-deficient murine B lymphoma-derived subclone (P388-45/C) selected for its resistance to high dosage of the antitumor drug camptothecin, we show that Topo I depletion results in the hypophosphorylation of SR proteins and impairs exonic splicing enhancer (ESE)-dependent but not constitutive splicing. The Affymetrix GeneChip system analysis revealed that several alternatively spliced genes, characterized by small exons and large introns, are down-regulated in Topo I-deficient cells. Given that ectopic expression of green fluorescent protein-Topo I fusion in Topo I-deficient cells restores both wild-type phosphorylation of SR proteins and ESE-dependent splicing, we conclude that Topo I-mediated phosphorylation plays a specific role in ESE-regulated splicing.

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