Pre-mRNA Splicing for Treatment of Human Disease

Human life depends on pre-mRNA splicing for cellular viability, differentiation and responses to changing physiology or environment. A major focus of my laboratory is to understand at a molecular level how the splicing machinery identifies sites for excision from gene transcript RNAs, which in turn changes the proteins produced. We have characterized the three-dimensional shapes of human splicing proteins recognizing one another and the gene transcript RNA at high resolution by X-ray crystallography (e.g. diagram above) complemented by molecular biology in human cells. Through this research, we identify a network of interactions responsible for recognizing human splice sites. The broader impact of this work for human disease is emphasized by the severe defects in pre-mRNA splicing that accompany most human hematologic malignancies and many metabolic disorders, as well as the dependence of HIV-1 and other complex retroviruses on RNA splicing for infectivity.