期刊
GENES & DEVELOPMENT
卷 25, 期 5, 页码 445-459出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.2014311
关键词
spliceostatin A; U2 snRNP; branch point; splicing fidelity; alternative splicing
资金
- Fundacion Marcelino Botin
- Fundacion Alicia Koplowicz
- AICR
- EURASNET
- Ministerio de Ciencia e Innovacion
- Consolider-Ingenio RNAREG
- Spanish Ministerio de Ciencia e Innovacion
- ICREA Funding Source: Custom
Spliceostatin A (SSA) is a stabilized derivative of a Pseudomonas bacterial fermentation product that displays potent anti-proliferative and anti-tumor activities in cancer cells and animal models. The drug inhibits pre-mRNA splicing in vitro and in vivo and binds SF3b, a protein subcomplex of U2 small nuclear ribonucleoprotein (snRNP), which is essential for recognition of the pre-mRNA branch point. We report that SSA prevents interaction of an SF3b 155-kDa subunit with the pre-mRNA, concomitant with nonproductive recruitment of U2 snRNP to sequences 59 of the branch point. Differences in base-pairing potential with U2 snRNA in this region lead to different sensitivity of 39 splice sites to SSA, and to SSA-induced changes in alternative splicing. Indeed, rather than general splicing inhibition, splicing-sensitive microarray analyses reveal specific alternative splicing changes induced by the drug that significantly overlap with those induced by knockdown of SF3b 155. These changes lead to down-regulation of genes important for cell division, including cyclin A2 and Aurora A kinase, thus providing an explanation for the anti-proliferative effects of SSA. Our results reveal a mechanism that prevents nonproductive base-pairing interactions in the spliceosome, and highlight the regulatory and cancer therapeutic potential of perturbing the fidelity of splice site recognition.
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