My laboratory has two major research focuses. The first is to understand the molecular mechanism of pre-mRNA splicing using a combination of X-ray crystallography, molecular biology, biochemistry and yeast genetics approaches. Splicing of pre-mRNA is essential for gene expression in all eukaryotes. In higher eukaryotes such as mammals, an average of 95% of the nucleotides in the primary transcript (pre-mRNA) of a protein-encoding gene are introns. These introns need to be precisely removed by splicing before the mRNA can be transported out of the nucleus and translated. Even a single nucleotide error can cause catastrophic consequences. It has also become increasingly clear that alternative splicing is a fundamental approach for eukaryotic gene expression regulation. Aberrant splicing contributes to at least 15% of human genetic disorders and causes many other diseases such as cancer. A thorough understanding of the pre-mRNA splicing pathway may provide useful approaches for human disease therapy. The splicing of pre-mRNA is carried out through two transesterification reactions catalyzed by the spliceosome, a huge macromolecular complex that contains five RNAs and numerous (over 145 in human) protein splicing factors. Using a combination of structural biology, molecular biology, biochemistry, and yeast genetics approaches, our goal is to understand how introns are recognized, spliceosomes assembled, and splicing catalyzed and regulated.
Our second research area focuses on identifying inhibitors of the Six1/Eya transcriptional complex for anti-breast cancer drug design. Transcription factor Six1 and its co-activator Eya are important for the development of many organs. Six1 and Eya are typically down-regulated after organ development is complete but are abnormally over-expressed in over 50% of primary breast tumors and over 90% of metastatic lesions. The over-expression of Six1 and Eya has a causal relationship with the initiation and metastatic development of breast cancer. Our goal is to identify small molecule inhibitors of the Six1/Eya transcriptional complex using both high throughput screening and structure-based drug design approaches. Since Six1 and Eya are typically not needed in normal adult tissues, compounds targeting this complex may be effective anti-breast cancer therapeutics with limited side effects.