Structural basis for specific RNA splicing correction induced by a small molecule
Small molecules that correct the splicing of the SMN2 gene have the potential to treat spinal muscular atrophy, the major genetic cause of infantile death. A recent "Nature Chemical Biology" paper by the Allain group (IMBB) sheds light on the mode of action of the gene-specific SMN2 splicing modifier.
SMN2 splicing modifiers act at the pre-mRNA splicing level when the U1 snRNA base pairs with the weak 5’-splice site of exon 7 to initiate spliceosome assembly. The Allain group's structural investigations of the complex formed by the RNA duplex (U1 snRNA /5’-SS) and the small molecule revealed that the splicing modifier inserts the major groove at the exon-intron junction close to a bulge adenine -1. The structure of the RNA-small molecule complex reveals that the splicing modifier stabilizes the unpaired adenine at the last position of the exon. Consequently, the minor groove of the RNA helix become more accessible for the binding of U1-C and the small molecule allosterically stimulates the assembly of the spliceosome on SMN2 exon7. This study uncovered a novel concept for specific splicing correction that we coined 5’-splice bulge repair and could be used to improve the current molecules or to design new splicing modifiers on other 5’-splice site variants.
Link to the publication in external page Nature Chemical Biology.