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

doi:10.1038/nchembio.2007.18

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

Nat Chem Biol. 2007 Sep;3(9):576-83. doi: 10.1038/nchembio.2007.18. Epub 2007 Jul 22.

Authors

Daisuke Kaida¹, Hajime Motoyoshi, Etsu Tashiro, Takayuki Nojima, Masatoshi Hagiwara, Ken Ishigami, Hidenori Watanabe, Takeshi Kitahara, Tatsuhiko Yoshida, Hidenori Nakajima, Tokio Tani, Sueharu Horinouchi, Minoru Yoshida

Affiliation

¹ Chemical Genetics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.

PMID: 17643111
DOI: 10.1038/nchembio.2007.18

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Active Transport, Cell Nucleus / drug effects*
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Humans
Phosphoproteins / antagonists & inhibitors*
Phosphoproteins / genetics
Pyrans / pharmacology
RNA Precursors / drug effects*
RNA Precursors / metabolism
RNA Splicing / drug effects*
RNA Splicing Factors
RNA, Small Interfering / pharmacology
RNA-Binding Proteins
Ribonucleoprotein, U2 Small Nuclear / antagonists & inhibitors*
Ribonucleoprotein, U2 Small Nuclear / genetics
Spiro Compounds / pharmacology

Substances

Antineoplastic Agents
FR 901464
Phosphoproteins
Pyrans
RNA Precursors
RNA Splicing Factors
RNA, Small Interfering
RNA-Binding Proteins
Ribonucleoprotein, U2 Small Nuclear
SF3B1 protein, human
SF3B2 protein, human
SF3B3 protein, human
SF3B4 protein, human
Spiro Compounds

Associated data

PubChem-Substance/24844207
PubChem-Substance/24844208
PubChem-Substance/24844209
PubChem-Substance/24844210
PubChem-Substance/24844211
PubChem-Substance/24844212
PubChem-Substance/24844213
PubChem-Substance/24844214
PubChem-Substance/24844215
PubChem-Substance/24844216
PubChem-Substance/24844217