Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA

Daisuke Kaida, Hajime Motoyoshi, Etsu Tashiro, Takayuki Nojima, Masatoshi Hagiwara, Ken Ishigami, Hidenori Watanabe, Takeshi Kitahara, Tatsuhiko Yoshida, Hidenori Nakajima, Tokio Tani, Sueharu Horinouchi, Minoru Yoshida

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393 Citations (Scopus)

Abstract

The removal of intervening sequences from transcripts is catalyzed by the spliceosome, a multicomponent complex that assembles on the newly synthesized pre-mRNA. Pre-mRNA translation in the cytoplasm leads to the generation of aberrant proteins that are potentially harmful. Therefore, tight control to prevent undesired pre-mRNA export from the nucleus and its subsequent translation is an essential requirement for reliable gene expression. Here, we show that the natural product FR901464 (1) and its methylated derivative, spliceostatin A (2), inhibit in vitro splicing and promote pre-mRNA accumulation by binding to SF3b, a subcomplex of the U2 small nuclear ribonucleoprotein in the spliceosome. Importantly, treatment of cells with these compounds resulted in leakage of pre-mRNA to the cytoplasm, where it was translated. Knockdown of SF3b by small interfering RNA induced phenotypes similar to those seen with spliceostatin A treatment. Thus, the inhibition of pre-mRNA splicing during early steps involving SF3b allows unspliced mRNA leakage and translation.

Original languageEnglish
Pages (from-to)576-583
Number of pages8
JournalNature Chemical Biology
Volume3
Issue number9
DOIs
Publication statusPublished - 2007 Sep

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Kaida, D., Motoyoshi, H., Tashiro, E., Nojima, T., Hagiwara, M., Ishigami, K., Watanabe, H., Kitahara, T., Yoshida, T., Nakajima, H., Tani, T., Horinouchi, S., & Yoshida, M. (2007). Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA. Nature Chemical Biology, 3(9), 576-583. https://doi.org/10.1038/nchembio.2007.18