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.
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.
|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|
|Landino, Jennifer; Norris, Stephen R; Li, Muyi et al. (2017) Two mechanisms coordinate the recruitment of the chromosomal passenger complex to the plane of cell division. Mol Biol Cell 28:3634-3646|
|Reinemann, Dana N; Sturgill, Emma G; Das, Dibyendu Kumar et al. (2017) Collective Force Regulation in Anti-parallel Microtubule Gliding by Dimeric Kif15 Kinesin Motors. Curr Biol 27:2810-2820.e6|
|Chen, Geng-Yuan; Kang, You Jung; Gayek, A Sophia et al. (2017) Eg5 Inhibitors Have Contrasting Effects on Microtubule Stability and Metaphase Spindle Integrity. ACS Chem Biol 12:1038-1046|
|Pfaltzgraff, Elise R; Roth, Gretchen M; Miller, Paul M et al. (2016) Loss of CENP-F results in distinct microtubule-related defects without chromosomal abnormalities. Mol Biol Cell 27:1990-9|
|Sturgill, Emma G; Norris, Stephen R; Guo, Yan et al. (2016) Kinesin-5 inhibitor resistance is driven by kinesin-12. J Cell Biol 213:213-27|
|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|
|Shin, Yongdae; Du, Yaqing; Collier, Scott E et al. (2015) Biased Brownian motion as a mechanism to facilitate nanometer-scale exploration of the microtubule plus end by a kinesin-8. Proc Natl Acad Sci U S A 112:E3826-35|
|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|
Showing the most recent 10 out of 18 publications