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     My lab studies two regulatory systems essential in maintaining genome stability and preventing tumor progression in certain types of cancers.  We primarily study the “spindle assembly checkpoint” (SAC) in the budding yeast Saccharomyces cerevisiae using a combination of genetic and molecular genetic approaches. The SAC is a regulatory mechanism that inhibits the onset of anaphase until all chromosomes achieve bipolar orientation on the spindle.  We have a poor understanding about how the spindle signal is generated and two general models that can be considered. The first is that the lack of tension is the initiating event and this model has almost completely dominated the field. The best data has come from studies of grasshoppers and mantid spermatocytes because they have large chromosomes that can be micromanipulated. The data clearly show that the lack of tension on detached chromosomes activates the spindle checkpoint however the mechanism may be restricted to meiotic cells. The second possibility is that the checkpoint monitors microtubule occupancy and if a kinetochore is unoccupied, then the cells arrest in mitosis. Recent data has suggested that mitotic cells monitor the state of microtubule occupancy and not tension.

       Both models can accommodate a role for the kinetochore in generating the SAC signal.  We have provided definitive evidence for a role of the kinetochore in checkpoint signaling in yeast. Several kinetochore mutants lack the spindle checkpoint and we have recently used a two-hybrid approach to make the connection between spindle checkpoint proteins and kinetochore proteins.  We have also identified new kinetochore proteins that have a role in the checkpoint and may be the key determinants for distinguishing tension from occupancy.  We have collaborated with Todd's lab to show that it is evolutionarily conserved to humans.

    We have recently shown that there is crosstalk between the SAC and the DNA damage checkpoint.  Certain types of DNA damage activate the the SAC independently of the kinetochore.  We are currently using a combination of genetics, genomics, biochemistry and cell biology to dissect the process.

    We have used a functional genomic approach to identify novel genes required for chromosome segregation and mitotic regulation. There is a wealth of large data sets that are publicly available and we are using computational tools to mine the tools and gain new insights into the roles that these novel proteins play in mitosis and the networks of other processes that impinge on mitotic regulation.

    Finally, we are collaborating with Dr. Dan Engel (Dept. of Microbiology) using genetic and genomic tools to identify novel targets of viral proteins with the long-term goal of developing novel anti-viral therapies.

 

 

 

This page last modified 08/11/2011

The Stukenberg Lab and the Burke Lab are in the Department of Biochemistry and Molecular Genetics at the University of Virginia