Molecular Analysis of the Kinetochore

University Of Washington, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): The transmission of genetic material in each cell division requires its accurate duplication and distribution to the daughter cells. Errors in this process lead to aneuploidy, which is implicated in oncogenesis, birth defects and cell death. The chromosomes are segregated into two equivalent parts by a microtubule- based molecular machine, the mitotic spindle. The spindle is bipolar with each pole carrying an exact complement of chromosomes to each daughter cell. Chromosomes attach to microtubules via multiprotein organelles called kinetochores. The kinetochore is at the center of both an error correction mechanism and the spindle checkpoint, which delays the cell cycle as long as unattached kinetochores remain. Kinetochores attach to microtubules with a striking combination of strength and plasticity. The attachments are mobile and robust under tension, but can also rapidly destabilize in response to regulatory signals. The binding strength of a native kinetochore is greater than that provided by the sum of its components. We will use reconstitution to test hypotheses for how the attachment strength is enhanced. Kinetochores transmit force from the end of the microtubule to the centromere. A model for the connectivity of the complexes within an assembled kinetochore has been proposed based on data gathered from multiple organisms. We propose to test this model and map the chain of connections that transmit force. Finally, we will test hypotheses for how incorrect attachments are detected and corrected.