The replicated genome must be accurately distributed to daughter cells during cell division. Subtle errors in this process lead to birth defects and likely contribute to the genesis of cancer. Severe defects in genome distribution lead to cell lethality and their induction using drugs targeting microtubules, the protein polymers that are a central component of the genome distribution machinery, is a widely used strategy in cancer chemotherapy. A major player in genome distribution during cell division is the kinetochore, a proteinaceous machine built on the centromere regions of mitotic chromosomes to generate a dynamic interface with spindle microtubules. The mechanical properties of kinetochore-microtubule interactions direct chromosome alignment and segregation on the spindle. The mechanics at this interface are tightly integrated with signaling pathways that detect and correct errors in the geometry of chromosome-spindle microtubule attachments and prevent cell cycle progression until all chromosomes are properly connected. These regulatory pathways are central to accurate inheritance of the genome as they ensure that replicated chromosomes are precisely divided into the two daughter cells. The ubiquitously conserved KNL-1/Mis12 complex/Ndc80 complex (KMN) protein network is proposed to play a central role at the kinetochore-microtubule interface. This protein network provides the core microtubule-binding activity of the kinetochore, primarily through a microtubule- binding surface on the 4-subunit Ndc80 complex. The KMN network additionally plays an important role in the spindle checkpoint-the kinetochore-anchored regulatory pathway that generates a """"""""wait anaphase'signal until all of the chromosomes in a cell are correctly attached to the spindle. The proposed work will focus on defining the mechanisms by which the KNL-1 subunit of the KMN network functions as a scaffold coordinating outer kinetochore assembly, microtubule attachment, and checkpoint signaling. The mechanism of microtubule binding by the KMN network and the functional interactions between the two distinct microtubule-binding activities in this protein set, which reside in the Ndc80 complex and in KNL-1, will also be analyzed using a combination of structural and biochemical approaches. In cells, kinetochore-bound spindle microtubules are significantly stabilized. To determine the extent to which the KMN network contributes to this property, the regulation of microtubule polymerization dynamics by the KMN network will be investigated in vitro. The KMN network is closely associated with, and in some cases directly contacts, kinetochore-localized kinases and phosphatases that are implicated in accurate chromosome segregation. The functions of this localized phosphate flux anchored to the KMN network in chromosome segregation and checkpoint signaling will also be addressed.
Errors in distributing the genome during cell division lead to birth defects and contribute to the genesis of cancer. The cellular machinery used for genome distribution is a common target in cancer chemotherapy. This project will focus on understanding the mechanisms that ensure accurate distribution of the genome to daughter cells during cell division. Elucidation of these mechanisms will contribute to our understanding of the development and progression of cancer and provide new avenues for therapeutic development.
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