title: FRG1P-mediated aggregation of proteins involved in pre-mRNA processing.
abstract: FRG1 is considered a candidate gene for facioscapulohumeral muscular dystrophy (FSHD) based on its location at chromosome 4qter and its upregulation in FSHD muscle. The FRG1 protein (FRG1P) localizes to nucleoli, Cajal bodies (and speckles), and has been suggested to be a component of the human spliceosome but its exact function is unknown. Recently, transgenic mice overexpressing high levels of FRG1P in skeletal muscle were described to present with muscular dystrophy. Moreover, upregulation of FRG1P was demonstrated to correlate with missplicing of specific pre-mRNAs. In this study, we have combined colocalization studies with yeast two-hybrid screens to identify proteins that associate with FRG1P. We demonstrate that artificially induced nucleolar aggregates of VSV-FRG1P specifically sequester proteins involved in pre-mRNA processing. In addition, we have identified SMN, PABPN1, and FAM71B, a novel speckle and Cajal body protein, as binding partners of FRG1P. All these proteins are, or seem to be, involved in RNA biogenesis. Our data confirm the presence of FRG1P in protein complexes containing human spliceosomes and support a potential role of FRG1P in either splicing or another step in nuclear RNA biogenesis. Intriguingly, among FRG1P-associated proteins are SMN and PABPN1, both being involved in neuromuscular disorders, possibly through RNA biogenesis-related processes.
authors.affiliation: Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands. s.vankoningsbruggen@dundee.ac.uk
authors.forename: Silvana
authors.initials: S
authors.lastname: van Koningsbruggen
authors.forename: Kirsten R
authors.initials: KR
authors.lastname: Straasheijm
authors.forename: Ellen
authors.initials: E
authors.lastname: Sterrenburg
authors.forename: Natascha
authors.initials: N
authors.lastname: de Graaf
authors.forename: Hans G
authors.initials: HG
authors.lastname: Dauwerse
authors.forename: Rune R
authors.initials: RR
authors.lastname: Frants
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002460:Cell Line; D002466:Cell Nucleolus / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008840:Microfilament Proteins; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D020107:Troponin T / Q000235:genetics / Q000378:metabolism; D020798:Two-Hybrid System Techniques
chemical_list: C101270:FRG1 protein, human; C484440:Frg1 protein, mouse; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D011506:Proteins; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; C518660:TNNT3 protein, human; D020107:Troponin T