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

Cell Chem Biol. 2021 Sep 16;28(9):1356-1365.e4. doi: 10.1016/j.chembiol.2021.03.002. Epub 2021 Mar 29.


RNA splicing, a highly conserved process in eukaryotic gene expression, is seen as a promising target for anticancer agents. 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 chemical splicing inhibition on long non-coding RNAs (lncRNAs) has been poorly understood. Here, we demonstrate that spliceostatin A (SSA), a chemical splicing modulator that binds to the SF3B subcomplex of the U2 small nuclear ribonucleoprotein particle (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.

Keywords: MALAT1; RNA-seq; pre-mRNA splicing; spliceostatin A.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Female
  • HeLa Cells
  • Humans
  • Phosphoproteins / antagonists & inhibitors*
  • Phosphoproteins / chemistry
  • Phosphoproteins / metabolism
  • Polyadenylation / drug effects
  • Pyrans / chemistry
  • Pyrans / pharmacology*
  • RNA Splicing / drug effects
  • RNA Splicing Factors / antagonists & inhibitors*
  • RNA Splicing Factors / chemistry
  • RNA Splicing Factors / metabolism
  • RNA, Long Noncoding / metabolism*
  • Ribonucleoprotein, U1 Small Nuclear / antagonists & inhibitors*
  • Ribonucleoprotein, U1 Small Nuclear / chemistry
  • Ribonucleoprotein, U1 Small Nuclear / metabolism
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Tumor Cells, Cultured


  • MALAT1 long non-coding RNA, human
  • Phosphoproteins
  • Pyrans
  • RNA Splicing Factors
  • RNA, Long Noncoding
  • Ribonucleoprotein, U1 Small Nuclear
  • SF3B1 protein, human
  • Spiro Compounds
  • spliceostatin A