UC Santa Cruz

Human gene expression is a complicated process, and when things go wrong, disease may arise. Many diseases such as cancer arise from abnormal gene expression, so understanding the components of our cells that help facilitate normal gene expression is essential. My research focuses on the component known as the spliceosome, a very dynamic and complex molecular machine of ribonucleic acids and proteins. Splicing is a choreographed routine as there are many moving components. SF3B inhibitors target components of the spliceosome and interfere with spliceosome assembly and stability. I hypothesize that the inhibition and instability may be linked to differences in RNA arrangements in the inhibitor stalled complex and A-complex. My dissertation focuses on three goals: First, I investigated the connection between structural rearrangements in U2 snRNA and the mechanism of SF3B inhibitors that target the U2 snRNP. Second, I characterized the intrinsic capabilities of U2 snRNA to adopt different secondary structures. Last, I employed a bimolecular exon ligation reaction to test if SF3B inhibitors interfere with exon ligation. My studies have demonstrated that SF3B inhibitors do not affect U2 snRNA structure in the spliceosome and the snRNP, and the U2 snRNA has an intrinsic ability to adopt alternate and possibly novel structures than previously predicted. The basic research I conduct will ultimately inform therapeutic research to generate treatments for diseases.