FRG1P-mediated aggregation of proteins involved in pre-mRNA processing |
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Authors: | Silvana van Koningsbruggen Kirsten R Straasheijm Ellen Sterrenburg Natascha de Graaf Hans G Dauwerse Rune R Frants Silvère M van der Maarel |
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Institution: | (1) Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Bldg. 2; room S-03-042, Postal zone 5-3-P, P.O. Box 9600, 2300 RC Leiden, Netherlands |
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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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