Daniel J. Burke, PhD
The mitotic spindle checkpoint and its deregulation in cancer
The Burke lab studies a mitotic regulatory system that is essential in maintaining genome stability and preventing tumor progression in certain types of cancers. They study the "spindle checkpoint" in the budding yeast using a combination of genetic and molecular genetic approaches. There are seven genes identified as components of the checkpoint and human homologs for all of the genes have been identified. Spindle checkpoint genes are mutated in certain cancers. The lab has provided definitive evidence for a role of the kinetochore in checkpoint signaling as several kinetochore mutants lack the spindle checkpoint. They mapped the checkpoint activity of the kinetochore to two separate protein complexes and recently identified mutants that provide the direct link between the kinetochore and the spindle checkpoint. Biochemical and cell biological experiments support the genetic data and some anti-cancer chemotherapies employ compounds like taxol to inhibit cell division by activating the spindle checkpoint. Taxol and related drugs bind to and inhibit tubulin, a verified target of anti-cancer chemotherapy. The lab has developed a strain for high throughput screening of chemical compounds that utilize the spindle checkpoint to arrest the cell cycle. The goal is to find targets, other than tubulin for anti-cancer drugs. From a screen of 87,264 compounds they have identified 9 lead compounds that work through the spindle checkpoint and are effective in yeast and human cells. They have used a functional approach called synthetic genetic array analysis to identify 38 genes that encode potential molecular targets of the compounds. Each of the recombinant proteins have been purified and are being used to determine which compound binds to which protein by direct binding assays. The long-term goal is to develop more effective anti-cancer compounds that utilize the spindle checkpoint for therapeutic intervention.