Spliceostatin A interaction with SF3B limits U1 snRNP availability and causes premature cleavage and polyadenylation

RNA splicing is a highly conserved process in eukaryotic gene expression. Splicing is associated with other RNA processing steps such as transcription and nuclear export. However, our understanding of the interaction between splicing and other RNA regulatory mechanisms remains incomplete. Moreover, the impact of splicing on long non-coding RNAs (lncRNAs) has been under studied. Here, we demonstrate that Spliceostatin A (SSA), a chemical splicing modulator that binds to the SF3B subcomplex of the U2 snRNP, limits U1 snRNP availability in splicing, resulting in premature cleavage and polyadenylation of MALAT1, a nuclear lncRNA, as well as protein-coding mRNAs. Therefore, truncated transcripts are exported into the cytoplasm and translated, resulting in aberrant protein products. Our work demonstrates that active recycling of the splicing machinery maintains homeostasis of RNA processing beyond intron excision