Other Perelman School of Medicine Affiliations
Biochemistry and Molecular Biophysics Graduate Program
Pennsylvania Muscle Institute
M.S., Moscow State University, 1990
Ph.D., Univeristy of Colorado at Boulder, 1997
Dean's Small Grant Award, University of Colorado at Boulder, 1992 and 1993
17th Annual MBC Paper of the Year Award
ASCB Celldance 2008, 2nd place Video
American Societyfor Cell Biology (ASCB)
During cell division the chromosomes must segregate equally to ensure health and viability of two daughter cells. This vital goal is achieved by elaborate cytoskeletal machine, the mitotic spindle. First, spindle microtubules attach to kinetochores on duplicated sister chromosomes. When microtubules shorten, two identical sets of now separated chromosomes become transported to the opposite poles of a dividing cell, producing two genetically identical daughters. The main goal of the research in our lab is to understand the molecular mechanisms that produce force and accuracy for chromosome motions. This research is fundamentally important not only because cell division is a key process of cellular and developmental biology, but also because controlling the factors that ensure equal chromosome segregation is of great medical significance. Indeed, the mitotic spindle constitutes one of the major chemotherapeutic targets, so a rigorous understanding of the kinetochore-microtubule force-producing attachments might help to develop novel and more specific anticancer drugs.
Our work toward this goal relies on a combination of cell biological, biophysical and computational approaches. To identify the mechanism of force-generating activity at the kinetochore, we have taken advantage of a simple unicellular eukaryote, fission yeast cell, whose mitotic features are markedly similar to those of the mammalian cells. By using molecular genetic, cell biological and microscopy approaches we have established that conventional ATP-dependent motors are dispensable for chromosome-to-pole motion itself, although they are important for the accuracy of chromosome segregation. To test if the root cause for chromosome motion lies in the mechanochemical properties of microtubule polymers, we have turned to single-molecule methodologies and used laser tweezers in vitro to measure the forces that can be exerted by the shortening microtubules. Indeed, these disassembling polymers can exert plenty of force to explain chromosome motions in cells, but only if the shortening microtubule ends are harnessed appropriately to the kinetochore. The current focus has thus shifted towards studying the biomechanical design of kinetochore-localized nanomachnines that capture the energy from microtubule disassembly and provide lasting attachments to the shortening microtubule ends even under a significant load. Three types of such couplers, one based on a sleeve structure, one on a ring , and a third on elongated fibrils have now been proposed. There are no man-made or natural macro-devices that function analogously to these couplers, so understanding their principle mechanisms presents a significant conceptual challenge and requires multidisciplinary and multi-facet approaches.
Grishchuk, E.L., Molodtsov, M.I., Ataullakhanov, F.I., and J.R. McIntosh, Force production by disassembling microtubules. Nature 438: 384-388, 2005.
Grishchuk, E.L. and J.R. McIntosh. Microtubule depolymerization can drive poleward chromosome motion in fission yeast. EMBO J. 25(20):4888-96, 2006.
Grishchuk, E.L., Spiridonov, I.S. and J.R. McIntosh. Mitotic chromosome bi-orientation in fission yeast is enhanced by dynein and a minus-end-directed, kinesin-like protein. Mol. Biol. Cell 18(6):2216-25, 2007.
Efremov, A., Grishchuk, E.L., McIntosh, J. R. and F. I. Ataullakhanov In search of an optimal ring to couple microtubule depolymerization to processive chromosome motions. Proc. Natl. Acad. Sci. (USA) 104(48): 19017-22, 2007.
McIntosh, J.R., Grishchuk, E.L., Morphew, M., Efremov, A., Zhudenkov, K., V.A.Volkov, I.M. Cheeseman, A. Desai, Mastronarde, D., and F.I. Ataullakhanov. Fibrils connect microtubule tips with kinetochores: a mechanism to couple tubulin dynamics to chromosome motion. Cell 135: 322-33, 2008.
Grishchuk, E.L., Efremov, A.K., Volkov, VA, Spiridonov, I.S., Gudimchuk, N., Westermann, S., Drubin, D., Barnes, G., McIntosh, J.R. and F.I. Ataullakhanov. The Dam1 ring binds microtubules strongly enough to be a processive as well as energy-efficient coupler for chromosome motion. Proc. Natl. Acad. Sci. (USA) 105(40): 15423-8, 2008.
Welburn, J.P., Grishchuk, E.L., Backer, C.B., Wilson-Kubalek, E.M., Yates, J.R. and I. Cheeseman The human kinetochore Ska1 complex facilitates microtubule depolymerization-coupled motility. Dev. Cell 16(3): 374-385, 2009.
Grishchuk, E.L. Toward a comprehensive and quantitative understanding of intracellular microtubule organization. Mol. Systems Biology 5: 251, 2009.
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