Molecular Biology

A Stringent Policy of Exclusion

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Science  21 Dec 2007:
Vol. 318, Issue 5858, pp. 1835
DOI: 10.1126/science.318.5858.1835d

With 95 of its 115 exons subject to alternative mRNA splicing, the Down syndrome cell adhesion molecule (Dscam) gene in Drosophila surely deserves a place in the Guinness Book of Records, having the potential to form 38,016 protein variants. Remarkably, each Dscam isoform has the same overall structure, as the alternatively spliced exons form clusters, with only one exon from each cluster being included in the translated protein. Olson et al. have identified heterogeneous nuclear ribonucleoprotein hrp36 as a factor critical for the mutually exclusive splicing of the exon 6 cluster, which contains 48 distinct exons; in its absence, concatenated exon 6 variants are found in Dscam. Using a RIP-Chip assay, they show that hrp36 binds throughout the exon 6 cluster, where it prevents the binding of another class of splicing factors, the serine/arginine-rich (SR) proteins, which promote exon inclusion. The authors suggest that hrp36 masks selector sites located just 5′ of each exon variant, thus precluding SR binding, with the result that only one selector site can interact productively with the single docking site upstream of the entire exon 6 cluster. The mutually exclusive nature of the docking site-selector interaction then ensures that only one exon 6 variant is included in each Dscam mRNA. Intriguingly, hrp36 has no effect on splicing of the other variable exon clusters, indicating that another mechanism must determine their mutually exclusive splicing. — GR

Nat. Struct. Mol. Biol. 14, 1134 (2007).

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