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Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA
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Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA
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Journal Article
Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA
2007
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
Active Transport, Cell Nucleus - drug effects
/ Antineoplastic Agents - pharmacology
/ Humans
/ Phosphoproteins - antagonists & inhibitors
/ Ribonucleoprotein, U2 Small Nuclear - antagonists & inhibitors
/ Ribonucleoprotein, U2 Small Nuclear - genetics
/ RNA
/ RNA Precursors - drug effects
