期刊
NUCLEIC ACIDS RESEARCH
卷 41, 期 6, 页码 3819-3832出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkt063
关键词
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资金
- NIH [RO1 GM083187, P20RR020171, R01 GM076485]
- Foundation for Prader-Willi Research
- Binational Science Foundation (BSF), USA-Israel [2010508]
- Direct For Biological Sciences [1039914] Funding Source: National Science Foundation
- Div Of Biological Infrastructure [1039914] Funding Source: National Science Foundation
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [0843551] Funding Source: National Science Foundation
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.
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