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Nucleic Acids Res. 2013 Apr 1;41(6):3819-32. doi: 10.1093/nar/gkt063. Epub 2013 Feb 7.

Pyrvinium pamoate changes alternative splicing of the serotonin receptor 2C by influencing its RNA structure.

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1
Department of Molecular and Cellular Biochemistry, University of Kentucky, 741 South Limestone, Lexington, KY 40536, USA.

Abstract

The serotonin receptor 2C plays a central role in mood and appetite control. It undergoes pre-mRNA editing as well as alternative splicing. The RNA editing suggests that the pre-mRNA forms a stable secondary structure in vivo. To identify substances that promote alternative exons inclusion, we set up a high-throughput screen and identified pyrvinium pamoate as a drug-promoting exon inclusion without editing. Circular dichroism spectroscopy indicates that pyrvinium pamoate binds directly to the pre-mRNA and changes its structure. SHAPE (selective 2'-hydroxyl acylation analysed by primer extension) assays show that part of the regulated 5'-splice site forms intramolecular base pairs that are removed by this structural change, which likely allows splice site recognition and exon inclusion. Genome-wide analyses show that pyrvinium pamoate regulates >300 alternative exons that form secondary structures enriched in A-U base pairs. Our data demonstrate that alternative splicing of structured pre-mRNAs can be regulated by small molecules that directly bind to the RNA, which is reminiscent to an RNA riboswitch.

PMID:
23393189
PMCID:
PMC3616728
DOI:
10.1093/nar/gkt063
[Indexed for MEDLINE]
Free PMC Article
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