UC Santa Cruz

The accurate expression of human genes requires precursor messenger RNA (pre-mRNA) splicing. Pre-mRNA splicing removes superfluous sequences (introns) from pre-mRNA and ligates protein-coding regions (exons) to yield mature messenger RNA (mRNA). To catalyze this reaction, the spliceosome, a large ribonucleoprotein complex, must assemble de novo on each intron. The spliceosome is composed of five core uracil-rich small nuclear RNAs and hundreds of associated proteins. A critical early step in the spliceosome assembly pathway is the recognition of exon-intron boundaries. These demarcations are defined by conserved consensus splicing sequences at the 5´ and 3´ ends of an intron. The efficient recruitment of early spliceosomal components to these landmarks is determined by trans-regulatory splicing factors that bind and activate cis-regulatory sequences that function as splicing enhancers or silencers. Together, the dynamic interplays between splicing factors and splicing regulatory sequences establish exon definition, defining and regulating an exon’s identity for pre-mRNA splicing.

The exact mechanisms that control exon definition remain poorly understood due to cis- and trans-acting contextual and positional dependencies. The failure to correctly define exons is a problem that can result in aberrant pre-mRNA splicing, a phenomenon that underlies numerous human diseases. Gaps in knowledge of the possible mechanisms that may regulate an exon’s identity is a fundamental challenge that impedes the development of precision medicines for disease-linked exons.

Here, my thesis research addresses the fields’ gap in knowledge surrounding mechanisms that control exon definition in a human disease context. Namely, my work adds to the growing understanding that certain exons are indeed fragile and highly vulnerable to pathogenic mutations that dysregulate splicing regulatory sequences. More intriguingly, my accomplished research suggests RNA structures may play a central role in exon identity than previously appreciated. Additionally, my cumulative research activity presents a novel hypothesis that RNA structures may have clinical relevance as a therapeutic target for precision RNA drugs. For these reasons, I believe my thesis work advances our understanding of the molecular mechanisms that control exon definition fidelity, and has potential broader impacts on developing precision medicine for patients with unmet needs.