Article abstract
Nature Chemical Biology 3, 576 - 583 (2007)
Published online: 22 July 2007 | doi:10.1038/nchembio.2007.18
Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA
Daisuke Kaida1, Hajime Motoyoshi2, Etsu Tashiro1,8, Takayuki Nojima3, Masatoshi Hagiwara3, Ken Ishigami2, Hidenori Watanabe2, Takeshi Kitahara2,8, Tatsuhiko Yoshida4, Hidenori Nakajima5, Tokio Tani6, Sueharu Horinouchi4 & Minoru Yoshida1,4,7
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.
- Chemical Genetics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
- Department of Applied Biological Chemistry, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
- Department of Functional Genomics, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
- Department of Biotechnology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
- Drug Discovery Research, Fermentation Research Laboratories, Astellas Pharma Inc. 5-2-3 Tokodai, Tsukuba, Ibaraki 300-2698, Japan.
- Department of Biological Sciences, Graduate School of Science and Technology, Kumamoto University, 2-39-1 Kurokami, Kumamoto 860-8555, Japan.
- Japan Science and Technology Corporation, CREST Research Project, Kawaguchi, Saitama 332-0012, Japan.
- Present addresses: Department of Bioscience and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan (E.T.); Laboratory of Natural Product Chemistry Center for Basic Research, The Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan (T.K.).
Correspondence to: Minoru Yoshida1,4,7 e-mail: yoshidam@riken.jp
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