Rui Zhao, PhD

The mechanism of pre-mRNA splicing

Pre-mRNA splicing is an essential step in the gene expression pathway of all eukaryotes. Almost all human genes contain introns and over 90% of these genes are alternatively spliced, greatly increasing the gene coding capacity and constituting a fundamental approach of gene regulation. As a consequence, even a single nucleotide error in splicing lead to catastrophic consequences and at least 30% of human genetic disorders are related to splicing errors. Splicing is catalyzed by the spliceosome, a huge RNA-protein complex containing 5 snRNAs and over 100 proteins. The spliceosome undergoes dramatic conformational and compositional changes through the splicing cycles, forming at least 10 distinct complexes. Our goal is to understand the mechanism and regulation of pre-mRNA splicing and its role in disease processes, using a combination of structural biology (cryo-EM and crystallography), biochemistry, and genetic approaches.

The Six1/Eya transcriptional complex

The Six1 homeobox transcription factor and its co-activator Eya are crucial developmental regulators. Post-organogenesis, Six1 and Eya typically down-regulated. However, they are abnormally unregulated in many cancers, contributing to tumor initiation and development. In addition to being a transcriptional co-activator, Eya also contains a Tyr phosphatase activity in its C-terminal domain and interacts with the PP2A Ser/Thr phosphatase through its N-terminal domain, both contributing to the tumor-promotional properties of Eya. Our goal is to understand the structure and function of Six1/Eya and develop small molecule inhibitors that will cripple the function of Six1/Eya in tumors with limited side effect to normal tissues.