Inhibition of SF3B1 by molecules targeting the spliceosome results in massive aberrant exon skipping
Spliceosome
Exon skipping
Nonsense-Mediated Decay
DOI:
10.1261/rna.065383.117
Publication Date:
2018-05-29T15:30:16Z
AUTHORS (10)
ABSTRACT
The recent identification of compounds that interact with the spliceosome (sudemycins, spliceostatin A, and meayamycin) indicates these molecules modulate aberrant splicing via SF3B1 inhibition. Through whole transcriptome sequencing, we have demonstrated treatment Rh18 cells sudemycin leads to exon skipping as predominant event. This was also observed following reanalysis published RNA-seq data sets derived from HeLa after A exposure. These results are in contrast previous reports indicate intron retention major consequence Analysis junctions up-regulated by small indicated sequences were absent annotated human genes, suggesting events yielded novel RNA transcripts. Interestingly, length preferred downstream exons significantly longer than skipped exons, although there no difference between lengths introns flanking exons. reading frame aberrantly maintained a ratio 2:1:1, close cassette (3:1:1) present naturally occurring isoforms, negative selection nonsense-mediated decay (NMD) machinery for out-of-frame Accordingly, genes involved NMD RNAs encoding proteins process enriched both sets. Our findings, therefore, further elucidate mechanisms which inhibition modulates pre-mRNA splicing.
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