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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM086610-04
Application #
8463559
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Gindhart, Joseph G
Project Start
2010-05-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$290,367
Indirect Cost
$104,074
Name
Vanderbilt University Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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
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
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
Sturgill, Emma G; Ohi, Ryoma (2013) Microtubule-regulating kinesins. Curr Biol 23:R946-8
Sturgill, Emma G; Ohi, Ryoma (2013) Kinesin-12 differentially affects spindle assembly depending on its microtubule substrate. Curr Biol 23:1280-90
Walczak, Claire E; Gayek, Sophia; Ohi, Ryoma (2013) Microtubule-depolymerizing kinesins. Annu Rev Cell Dev Biol 29:417-41
Su, Xiaolei; Ohi, Ryoma; Pellman, David (2012) Move in for the kill: motile microtubule regulators. Trends Cell Biol 22:567-75

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