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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.
Document Type
Article
Publication Date
2-7-2013
Repository Citation
Shen, Manli; Bellaousov, Stanislav; Hiller, Michael; de La Grange, Pierre; Creamer, Trevor O.; Malina, Orit; Sperling, Ruth; Mathews, David H.; Stoilov, Peter; and Stamm, Stefan, "Pyrvinium pamoate changes alternative splicing of the serotonin receptor 2C by influencing its RNA structure" (2013). Molecular and Cellular Biochemistry Faculty Publications. 34.
https://uknowledge.uky.edu/biochem_facpub/34
Additional file 1
nar-03081-a-2012-File004.xlsx (3010 kB)
Additional file 2
nar-03081-a-2012-File005.xls (26460 kB)
Additional file 3
Notes/Citation Information
Published in Nucleic Acids Research, v. 41, no. 6, p. 3819-3832.
© The Author(s) 2013. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.