Human Molecular Genetics Advance Access published online on October 2, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm284
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Protein phosphatase 1 binds to the RNA recognition motif of several splicing factors and regulates alternative pre-mRNA processing
University of Erlangen, Institute for Biochemistry, Fahrstraße 17, 91054 Erlangen, Germany 1 ICREA and Centre de Regulacio Genomica; Passeig Maritim 37-49; 08003 Barcelona; Spain 2 Exonhit, ExonHit Therapeutics, 65 Boulevard Massena, 75013 Paris, France 3 Ohio State University, Department of Molecular and Cellular Biochemistry, 363 Hamilton Hall, 1645 Neil Avenue, Columbus OH 43210-1218 4 University of Missouri, Department of Veterinary Pathobiology, Life Sciences Center, 471G, 1201 Rollins Road, Columbia, MO 65211-7310 5 Laboratory of Biosignaling and Therapeutics, Department of Molecular Cell Biology, Faculty of Medicine, KULeuven, Belgium
* corresponding author: Stefan{at}stamms-lab.net phone: +49 9131 8524622 fax: +49 9131 8524605
Received June 25, 2007; Revised September 27, 2007; Accepted September 27, 2007
Alternative splicing emerges as one of the most important mechanisms to generate transcript diversity. It is regulated by the formation of protein complexes on premRNA. We demonstrate that protein phosphatase 1 (PP1) binds to the splicing factor transformer2-beta1 (tra2-beta1) via a phylogenetically conserved RVDF sequence located on the RNA recognition motif (RRM) of tra2-beta1. PP1 binds directly to tra2-beta1 and dephosphorylates it, which regulates the interaction between tra2-beta1 and other proteins. Eight other proteins, including SF2/ASF and SRp30c contain an evolutionary conserved PP1 docking motif in the beta-4 strand of their RRMs indicating that binding to PP1 is a new function of some RRMs. Reducing PP1 activity promotes usage of numerous alternative exons, demonstrating a role of PP1 activity in splice site selection. PP1 inhibition promotes inclusion of the survival of motoneuron 2 (SMN2) exon 7 in a mouse model expressing the human gene. This suggests that reducing PP1 activity could be a new therapeutic principle to treat spinal muscular atrophy and other diseases caused by missplicing events. Our data indicate that the binding of PP1 to evolutionary conserved motifs in several RRMs is the link between known signal transduction pathways regulating PP1 activity and pre-mRNA processing.
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