P. Todd Stukenberg
Primary AppointmentBiochemistry and Molecular Genetics
Mechanisms of chromosome segregation in Mitosis and generation of Chromosomal Instability in tumors
Defects in chromosome segregation can generate aneuploidy, a condition that is found in almost all human tumors and is the major cause of miscarriages and birth defects. The complex process of chromosome segregation must be highly regulated to ensure fidelity and prevent aneuploidy. In fact, in a large percentage of tumors the fidelity of mitosis is decreased which can drive tumor progression. Many of the events of mitosis are regulated by the kinetochores and the inner centromere. Kinetochore are assembled on centromeric DNA that bind microtubules and move chromosomes on the mitotic spindle. They also generate the spindle checkpoint signal the ensures that all of the kinetochores are bound to microtubules before they undergo anaphase segregation of chromatids. Inner centromeres are the chromosome region between kinetochores. They are the major site of cohesion between sister chromatids and also contain regulators of kinetochores. This cohesion must be maintained through metaphase and its dissolution is the critical event that triggers anaphase. How kinetochores and inner centromeres coordinate the events of mitosis underlie a number of critical unanswered questions with direct relevance to cancer biology. The Stukenberg lab studies the pathways that 1) power the movements of chromosome movement using the energy stored in the microtubule polymer 2) ensure that the microtubules bound to kinetochores emanate from the correct poles to properly segregate the two sister chromatids in anaphase 3) connect the attachments of microtubules to kinetochores with the generation of the spindle checkpoint signal 4) regulate the transcription from inner centromeres on mitotic chromosomes 5) lower the fidelity of segregation in tumors. Much of our work has focused on the Aurora B kinase which is a critical mitotic regulator that localizes to the inner centromere region from prophase to anaphase. Aurora kinases have become important drug targets for chemotherapeutics. We discovered that Aurora B regulates microtubule dynamics, microtubule attachments to kinetochores and the spindle checkpoint. We are dissecting how Aurora B is regulated and identifying the important substrates that are regulated by Aurora B for proper mitotic progression. The lab performed some of the initial characterization and identified the subunits of the Ndc80 complex, which is the key microtubule attachment point of kinetochores to microtubules. We demonstrated that the Ndc80 complex is required for proper kinetochore assembly, movements of chromosomes and generating the spindle checkpoint signals. We are studying the biophysics and cell biology of Ndc80 to understand how kinetochores move chromosomes and how the spindle checkpoint is coupled to microtubule attachments. We also study how tumors missegregate chromosomes at a higher rate than non-transformed cells, which is known as ?Chromosomal Instability?. We utilize bioinformatic approaches to dissect the changes in human tumors that cause the events and recapitulate those changes in model systems.