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.
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Acknowledgement
We thank Dr. A.I. Lamond, Dundee, UK, for critically reading the manuscript and Dr. M. Carmo-Fonseca, Lisbon, Portugal, for critically reading the manuscript and for providing us with several primary antibodies. Our research is funded by the Prinses Beatrix Fonds, the Muscular Dystrophy Association (USA), the Dutch FSHD Foundation, the Stichting Spieren voor Spieren, the National Institutes of Health (NIH-NIAMS; R21 AR4 8327-01), the European Union (QLTR-2000-01673 and LSHM-CT-2005-018675), the Shaw family, and FSH Society.
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van Koningsbruggen, S., Straasheijm, K.R., Sterrenburg, E. et al. FRG1P-mediated aggregation of proteins involved in pre-mRNA processing. Chromosoma 116, 53–64 (2007). https://doi.org/10.1007/s00412-006-0083-3
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DOI: https://doi.org/10.1007/s00412-006-0083-3