TY  - JOUR
A1  - Ji, Changhe
A1  - Bader, Jakob
A1  - Ramanathan, Pradhipa
A1  - Hennlein, Luisa
A1  - Meissner, Felix
A1  - Jablonka, Sibylle
A1  - Mann, Matthias
A1  - Fischer, Utz
A1  - Sendtner, Michael
A1  - Briese, Michael
T1  - Interaction of 7SK with the Smn complex modulates snRNP production
JF  - Nature Communications
N2  - Gene expression requires tight coordination of the molecular machineries that mediate transcription and splicing. While the interplay between transcription kinetics and spliceosome fidelity has been investigated before, less is known about mechanisms regulating the assembly of the spliceosomal machinery in response to transcription changes. Here, we report an association of the Smn complex, which mediates spliceosomal snRNP biogenesis, with the 7SK complex involved in transcriptional regulation. We found that Smn interacts with the 7SK core components Larp7 and Mepce and specifically associates with 7SK subcomplexes containing hnRNP R. The association between Smn and 7SK complexes is enhanced upon transcriptional inhibition leading to reduced production of snRNPs. Taken together, our findings reveal a functional association of Smn and 7SK complexes that is governed by global changes in transcription. Thus, in addition to its canonical nuclear role in transcriptional regulation, 7SK has cytosolic functions in fine-tuning spliceosome production according to transcriptional demand.
KW  - Molecular neuroscience
KW  - RNA
KW  - RNA splicing
KW  - Transcription
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259125
VL  - 12
IS  - 1
ER  - 
TY  - JOUR
A1  - Linder, Bastian
A1  - Hirmer, Anja
A1  - Gal, Andreas
A1  - Rüther, Klaus
A1  - Bolz, Hanno Jörn
A1  - Winkler, Christoph
A1  - Laggerbauer, Bernhard
A1  - Fischer, Utz
T1  - Identification of a PRPF4 Loss-of-Function Variant That Abrogates U4/U6.U5 Tri-snRNP Integration and Is Associated with Retinitis Pigmentosa
N2  - Pre-mRNA splicing by the spliceosome is an essential step in the maturation of nearly all human mRNAs. Mutations in six spliceosomal proteins, PRPF3, PRPF4, PRPF6, PRPF8, PRPF31 and SNRNP200, cause retinitis pigmentosa (RP), a disease characterized by progressive photoreceptor degeneration. All splicing factors linked to RP are constituents of the U4/U6.U5 tri-snRNP subunit of the spliceosome, suggesting that the compromised function of this particle may lead to RP. Here, we report the identification of the p.R192H variant of the tri-snRNP factor PRPF4 in a patient with RP. The mutation affects a highly conserved arginine residue that is crucial for PRPF4 function. Introduction of a corresponding mutation into the zebrafish homolog of PRPF4 resulted in a complete loss of function in vivo. A series of biochemical experiments suggested that p.R192H disrupts the binding interface between PRPF4 and its interactor PRPF3. This interferes with the ability of PRPF4 to integrate into the tri-snRNP, as shown in a human cell line and in zebrafish embryos. These data suggest that the p.R192H variant of PRPF4 represents a functional null allele. The resulting haploinsufficiency of PRPF4 compromises the function of the tri-snRNP, reinforcing the notion that this spliceosomal particle is of crucial importance in the physiology of the retina.
KW  - zebrafish
KW  - embryos
KW  - immunoprecipitation
KW  - arginine
KW  - messenger RNA
KW  - spliceosomes
KW  - mutation
KW  - RNA splicing
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-113663
ER  -