The faithful segregation of genetic material to daughter cells is essential for the survival of an organism. The cell must replicate the DNA of each of its chromosomes and distribute one copy to each of the two daughter cells. Chromosome segregation is mediated by the mitotic spindle, which is composed of a dynamic array of microtubules (MTs) and associated proteins. While the pathways for spindle assembly differ depending on the cell type, all spindles share common structural features. The MT minus ends are focused into two poles, while the more dynamic plus ends interact with chromosomes at the spindle equator. Proper spindle function relies on an underlying organization that is maintained by proteins that regulate spindle MT dynamics as well as by the motors that move the chromosomes and the MTs. Agents that alter the polymerization dynamics of MTs or motor function are effective in the treatment of multiple cancers. Therefore, elucidating the molecular mechanism of the regulation of MT dynamics and organization during spindle assembly will be crucial not only to our understanding of cell division but also for the generation of new anti-mitotic drugs to help combat cancer. Despite our understanding of many of the molecules that regulate spindle dynamics and organization, it is not known how these activities are coordinated during mitosis to insure proper spatial and temporal control. In the present proposal we will: 1) Define how phosphorylation controls the activity and spatial regulation of MCAK by testing the hypothesis that MCAK activity is regulated by conformational changes in the protein that are regulated both spatially and temporally throughout mitosis by the different phosphorylation modifications that occur on MCAK. 2) Define how changes in MT dynamics and sliding affect spindle organization and mitotic progression by testing the hypothesis that Kif18B and MCAK regulate astral MT dynamics at distinct times during spindle assembly. We will also test the model that both MT sliding and MT dynamics contribute to the regulation of spindle length by testing whether HSET or Kif18A perturbation alters spindle MT dynamics and contributes to mitotic progression. 3) Define the mechanisms by which MT dynamics and sliding affect spindle organization by elucidating the mechanistic basis of how the MT dynamics of the different MT subpopulations are differentially regulated and how these regulators alter the downstream targets that act on spindle organization. Together these studies will provide significant new insight into how MT dynamics and MT sliding activities are coordinated to insure proper mitotic progression.
The faithful segregation of genetic material by the mitotic spindle to daughter cells is essential for the survival of an organism. The spindle is composed of microtubules and associated proteins that are utilized to attach the chromosomes to the spindle and to ensure their accurate segregation. Given that the mitotic spindle is a target of numerous chemotherapeutic agents that specifically disrupt spindle MT dynamics, elucidating the mechanisms by which spindle microtubule dynamics are regulated has important implications for biomedical research.
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