Mechanisms of chromosome segregation and mitotic timing

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 DESCRIPTION (provided by applicant): This proposal aims to study the mechanism by which kinetochore proteins capture microtubules to ensure equal chromosome segregation and timely progression through mitosis. Through analyzing the spindle-associated lamin-B containing network, which we had referred to as the spindle matrix previously, we have made a number of exciting observations, which suggest that component(s) of the lamin-B network functions together with microtubules as chaperones for kinetochore proteins such as Bub3. These chaperones are required for kinetochore proteins to regulate proper microtubule and kinetochore interactions and timely mitosis progression. We propose to dissect the molecular mechanism by which these chaperones function in mitosis. Specifically, in Aim 1 we will dissect whether and how the interaction between BuGZ and microtubules and/or EB1 is required for Bub3 kinetochore loading and chromosome alignment. In Aim 2 we will study whether the destabilization of BuGZ and Bub3 by RanGTP contributes to silencing of the spindle assembly checkpoint (SAC). In Aim 3, we propose to study the molecular mechanisms that mediate end-on kinetochore-MT attachment and SAC silencing.