Chromosome Movement in Meiosis and Mitosis

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DESCRIPTION (provided by applicant): The long-term objectives of this project are to identify and characterize the forces that underlie chromosome movement in meiosis and mitosis, including interactions of the chromosomes with the spindle and microtubule dynamics involved in spindle assembly and function. A major goal is to understand the role of microtubule motor proteins in spindle and chromosome dynamics during cell division, including the molecular basis of motor directionality and force generation, and the importance of these motor properties in division. The proposed studies focus on Ncd, a minus-end kinesin microtubule motor protein of Drosophila. The Ncd motor plays an essential role in spindle assembly and function in meiosis and mitosis. The studies proposed here are to examine basic motor properties with the objective of understanding how motors work in the cell. The specific aims of the proposed studies are to 1. Determine the structural basis of motor directionality. The region of the Ncd motor that undergoes a conformational or angle change required for motor directionality will be determined. 2. Identify structural changes of the motor essential for function. Mutants that decouple motor functions or alter the nucleotide hydrolysis cycle will be analyzed to obtain crystal structures of new motor conformations and provide information about the motor mechanism. 3. Define factors essential for motor function in live cells. A mutant that converts the motor into a bidirectional motor in vitro will be analyzed in live cells to examine the hypothesis that motor directionality is essential to Ncd function in the spindle. These studies address the molecular basis of force generation in the spindle and the role of microtubule motors in chromosome movement during cell division. Defective chromosome distribution causes aneuploidy and other genetic abnormalities, and is associated with oncogenesis in humans.