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The U1 snRNP protein U1C and Helix H of U1 snRNA are critical for small molecule splicing modulator function

ABSTRACT: Risdiplam and branaplam are two small molecule splicing modulators that enhance the ability of U1 snRNP to recognize non-canonical GA/GU-containing 5’ splice sites (ss). We demonstrated that branaplam improves the recognition of these 5’ ss by reconstituted U1 snRNP in vitro and that this effect is dependent on the ZnF domain of U1C and Helix H of U1 snRNA but not U1A or U1-70K. We then showed in vivo depletion of U1C decreases the potency of most compound-induced cassette exons. However, many cassette exons only become responsive to compound when U1C is depleted, leading to a model where U1C stabilizes different context-dependent structural conformations of U1 snRNP which either promotes or hinders compound binding and its effect on splicing. Surprisingly, risdiplam has no effect on the recognition of these 5’ ss in vitro, suggesting additional cellular factors are required.

ORGANISM(S): Homo sapiens

PROVIDER: GSE304951 | GEO | 2026/07/24

REPOSITORIES: GEO

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Selected humanization of yeast U1 snRNP leads to global suppression of pre-mRNA splicing and mitochondrial dysfunction in the budding yeast

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