The correct distribution of genetic material during mitosis is essential for successful cell division. Proper chromosome segregation is regulated by the mitotic checkpoint, which blocks anaphase until all chromosomes are attached to spindle microtubules, and an additional signaling network that detects and corrects improper chromosome-microtubule attachments. Until recently, little was known about how the regulation of chromosome attachment was coordinated with the mitotic checkpoint. There is now definitive evidence to suggest that BubR1, a component of the mitotic checkpoint, is also required for correct attachments. My proposal takes a multi-disciplinary approach to examine the contributions of BubR1 to chromosome-microtubule attachments during cell division. Using a method known as extended tethering, I will develop and evaluate a chemical inhibitor of BubR1. A reversible inhibitor of BubR1 will be an excellent tool to probe the regulatory role of this protein during mitosis. The design of a chemical inhibitor is an ambitious goal and my proposal balances this risk with the use of siRNA, a method that has been used to reduce BubR1 expression levels, to further examine the function of this protein. ? ? ?
