Human Molecular Genetics Advance Access originally published online on October 2, 2007
Human Molecular Genetics 2008 17(1):52-70; 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
1 University of Erlangen, Institute for Biochemistry, Fahrstraße 17, Erlangen 91054, Germany 2 ICREA and Centre de Regulacio Genomica, Passeig Maritim 37–49, Barcelona 08003, Spain 3 Exonhit, ExonHit Therapeutics, 65 Boulevard Massena, Paris 75013, France 4 Department of Molecular and Cellular Biochemistry, Ohio State University, 363 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210-1218, USA 5 Life Sciences Center, Department of Veterinary Pathobiology, University of Missouri, 471G, 1201 Rollins Road, Columbia, MO 65211-7310, USA 6 Laboratory of Biosignaling and Therapeutics, Department of Molecular Cell Biology, Faculty of Medicine, KULeuven, Belgium 7 Department of Molecular and Cellular Biochemistry, 741 South Limestone, BBSRB, Lexington, KY 40536
* To whom correspondence should be addressed. Tel: +49 91318524622/8593230896; Fax: +49 91318524605/8593231037; Email: stefan{at}stamms-lab.net
Received June 25, 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 pre-mRNA. 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 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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