Spicing up splicing – with poison exons

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Regulatory networks in which proteins bind to DNA to alter gene expression are a well established feature of cell biology, but less is known about whether this concept is mirrored by proteins that form interactions with RNA.

In a new article published in Genome Biology, an international team of researchers led by Karla Neugebauer (Max Planck Institute of Molecular Cell Biology and Genetics) show that the RNA-binding protein SRSF3 sits at the heart of an extensive regulatory network.

Using state-of-the-art iCLIP technology developed by co-author Jernej Ule, the study begins with a detailed exploration of the RNA binding targets for SRSF3 and its close relative SRSF4, two proteins known to function in RNA splicing. A large number of interactions were identified, including with non-coding RNAs and, surprisingly, the intronless (and hence unsplicable) RNAs that encode histones. The histone finding in particular provides new evidence that splicing is just one of multiple mechanisms used by these proteins to regulate RNA.

But most intriguing was the observation that SRSF3 had a strong tendency to bind to transcripts encoding RNA-binding proteins, including members of its own SR gene family (the SRSF3 transcript itself being no exception). The authors show that the function of this SR transcript-binding phenomenon is to promote alternative splicing of a "poison" exon, which condemns the RNA to a fate of nonsense-mediated decay, and that the stability of SR protein levels is by this mechanism at the mercy of SRSF3.

The power SRSF3 holds over a diverse set of RNA binding proteins, most of which themselves have regulatory functions, likely renders it a key player in a broad range of regulatory cascades – and adds some enticing network spice to the cell biology of splicing.