Microtubules are unstable filaments that grow and shrink by subunit addition and loss. During mitosis, microtubules organize into a bilaterally symmetric apparatus termed the mitotic spindle which acts to segregate replicated chromosomes into two equal sets. Chemotherapeutic agents that interfere with mitotic spindle function are effective at eradicating cancer cells. Better understanding of the cell division process is likely to identify additional drug targets that are useful in cancer disease management. Chromosomes engage microtubules in the mitotic spindle through specialized structures called kinetochores. Growth and shortening of kinetochore-microtubules generate forces that power chromosome movement. Kinetochore-microtubule dynamics must be modulated to produce coordinated sister kinetochore movements, but little is known about the underlying mechanisms. In this grant, we will investigate the biochemical mechanism by which a kinetochore-localized motor protein affects microtubule polymerization dynamics. We will also address how one master regulator of mitosis, Polo like kinase 1, uses spindle forces as a cue to dictate chromosome movements. Our work will advance our knowledge of cell division mechanisms, and have immediate relevance to ongoing studies exploring the suitability of Polo kinases as cancer drug targets.

Public Health Relevance

During cell division, replicated chromosomes are segregated among two daughter cells through the action of a microtubule-based apparatus termed the mitotic spindle. Chromosome motility is powered by the polymerization dynamics of microtubule plus ends attached to kinetochores. Kinetochore-microtubule dynamics are subject to extensive regulation, and in this application, we will determine how two protein factors modulate microtubule dynamics to dictate the speed and directionality of mitotic chromosome movements.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
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Gindhart, Joseph G
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Vanderbilt University Medical Center
Anatomy/Cell Biology
Schools of Medicine
United States
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Chiang, Yun-Chen; Park, In-Young; Terzo, Esteban A et al. (2018) SETD2 Haploinsufficiency for Microtubule Methylation Is an Early Driver of Genomic Instability in Renal Cell Carcinoma. Cancer Res 78:3135-3146
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Landino, Jennifer; Ohi, Ryoma (2016) The Timing of Midzone Stabilization during Cytokinesis Depends on Myosin II Activity and an Interaction between INCENP and Actin. Curr Biol 26:698-706
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Sturgill, Emma G; Das, Dibyendu Kumar; Takizawa, Yoshimasa et al. (2014) Kinesin-12 Kif15 targets kinetochore fibers through an intrinsic two-step mechanism. Curr Biol 24:2307-13
Gayek, A Sophia; Ohi, Ryoma (2014) Kinetochore-microtubule stability governs the metaphase requirement for Eg5. Mol Biol Cell 25:2051-60

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