Nat. Commun. 8, 2100 (2017) https://doi.org/10.1038/s41467-017-02007-z
Alternative mRNA splicing is a highly regulated process that is often disrupted in cancer, wherein core components of the pre-mRNA splicing machinery may also be mutated. Several families of natural compounds display antitumor activity that is thought to depend on their action on core components of the pre-mRNA splicing machinery. In particular, spliceostatin A (SSA) and its synthetic derivatives meayamycin and the sudemycins were previously identified to target SFB1, which is involved in 3′ splice-site recognition. To gain detailed insights into how specific drugs modulate splicing and cancer cell viability, Vigevani et al. first established that sudemycin C1 can affect alternative splicing events of two genes—MCL1 and PDCD10—to different extents, and that the differential effect was imparted by specific sequences surrounding the splice sites. The authors next assessed the effect of the structurally related SSA and two sudemycins on transcriptome-wide splicing by sequencing both steady state and nascent RNA following drug treatment. Although SSA was more potent than the sudemycins for inducing exon skipping, the sudemycins had a stronger effect on the process, and those effects were modulated by sequence context. Though the precise molecular mechanisms behind these drug-specific effects on splicing remain unclear, the results suggest that it may be possible to identify drugs that selectively regulate splicing to be therapeutically beneficial.
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Larochelle, S. Making the cut. Nat Chem Biol 14, 107 (2018). https://doi.org/10.1038/nchembio.2564