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Nucleic Acids Res. 2019 Apr 23;47(7):3667-3679. doi: 10.1093/nar/gkz036.

A high-throughput screen identifies small molecule modulators of alternative splicing by targeting RNA G-quadruplexes.

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Lester & Sue Smith Breast Center, Department of Molecular & Human Genetics, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.


RNA secondary structures have been increasingly recognized to play an important regulatory role in post-transcriptional gene regulation. We recently showed that RNA G-quadruplexes, which serve as cis-elements to recruit splicing factors, play a critical role in regulating alternative splicing during the epithelial-mesenchymal transition. In this study, we performed a high-throughput screen using a dual-color splicing reporter to identify chemical compounds capable of regulating G-quadruplex-dependent alternative splicing. We identify emetine and its analog cephaeline as small molecules that disrupt RNA G-quadruplexes, resulting in inhibition of G-quadruplex-dependent alternative splicing. Transcriptome analysis reveals that emetine globally regulates alternative splicing, including splicing of variable exons that contain splice site-proximal G-quadruplexes. Our data suggest the use of emetine and cephaeline for investigating mechanisms of G-quadruplex-associated alternative splicing.

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