Protein phosphatase 1 binds to the RNA recognition motif of several splicing factors and regulates alternative pre-mRNA processing

Tatyana Novoyatleva, Bettina Heinrich, Yesheng Tang, Natalya Benderska, Matthew E.R. Butchbach, Christian L. Lorson, Monique A. Lorson, Claudia Ben-Dov, Pascale Fehlbaum, Laurent Bracco, Arthur H.M. Burghes, Mathieu Bollen, Stefan Stamm

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)52-70
Number of pages19
JournalHuman Molecular Genetics
Volume17
Issue number1
DOIs
StatePublished - Jan 1 2008

Bibliographical note

Funding Information:
This work was supported by the European Union, EURASNET (S.S., CBD), the German Research Council (S.S.), the BMBF (S.S.), the families of SMA (FSMA to S.S. and MERB), the German Cancer Aid (S.S.) and the National Institutes of Health (NIH grant 3860 to A.H.M.B.).

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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