Amazing stuff!
"... The blueprint reveals that individual components of the spliceosome are far more specialized than previously thought. Many of these components have not been considered for drug development before because their specialized functions were unknown. The discovery can unlock new treatments that are more effective and have fewer side effects. ...
The spliceosome is the collection of 150 different proteins and five small RNA molecules which orchestrate the editing process, but until now, the specific roles of its numerous components were not fully understood. The team at the CRG altered the expression of 305 spliceosome-related genes in human cancer cells one by one, observing the effects on splicing across the entire genome. ..."
From the editor's summary and abstract:
"Editor’s summary
Nucleated cells have evolved a complex molecular machinery to remove internal sequences known as introns from the primary RNA transcripts of genes. This splicing process is necessary for the translation of gene messages into proteins and allows the production of alternative mRNAs and proteins from individual genes. After individually lowering the expression of more than 300 genes encoding components of the intron-removing machinery, Rogalska et al. analyzed the effects on alternative RNA splicing and inferred functional similarities and mutual influences. The spliceosome’s intricate complexity provides multiple built-in regulatory mechanisms, and these results offer a resource with which to determine their operation in physiology and disease. ...
Abstract
The spliceosome is the complex molecular machinery that sequentially assembles on eukaryotic messenger RNA precursors to remove introns (pre-mRNA splicing), a physiologically regulated process altered in numerous pathologies. We report transcriptome-wide analyses upon systematic knock down of 305 spliceosome components and regulators in human cancer cells and the reconstruction of functional splicing factor networks that govern different classes of alternative splicing decisions. The results disentangle intricate circuits of splicing factor cross-regulation, reveal that the precise architecture of late-assembling U4/U6.U5 tri–small nuclear ribonucleoprotein (snRNP) complexes regulates splice site pairing, and discover an unprecedented division of labor among protein components of U1 snRNP for regulating exon definition and alternative 5′ splice site selection. Thus, we provide a resource to explore physiological and pathological mechanisms of splicing regulation."
First blueprint of the human spliceosome (original news release)
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