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


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.

SUBMITTER: Shen M 

PROVIDER: S-EPMC3616728 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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

Shen Manli M   Bellaousov Stanislav S   Hiller Michael M   de La Grange Pierre P   Creamer Trevor P TP   Malina Orit O   Sperling Ruth R   Mathews David H DH   Stoilov Peter P   Stamm Stefan S  

Nucleic acids research 20130207 6


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 p  ...[more]

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