Protein RNA Rearrangements in the Spliceosome

PROJECT NARRATIVE / PUBLIC HEALTH RELEVANCE STATEMENT Excision of introns from pre-mRNA is critical in the pathway of gene expression. This excision occurs within spliceosomes and requires precise recognition – during both spliceosome assembly and splicing catalysis – of three sites (two splice sites and a branch site) to appropriately join exonic coding sequences. Mutations in components of the U2 snRNP are implicated in myelodysplastic syndrome (MDS) and other cancers, and mutations that alter snRNP levels underlie spinal muscular atrophy (SMA). The roles of small molecule IP6 and mutations in U2 snRNA, identified here, have not previously been investigated. Our studies will provide a better understanding of U2 snRNPs, their interactions with the RNA ligands that are substrates for catalysis, and how disease-related mutations alter this process.