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Sophie Dumont Ph.D.

Mechanics of chromosome segregation

Sophie Dumont Ph.D.

During cell division, each daughter cell must inherit exactly one copy of the chromosome. Errors can lead to cell death or cancer in somatic cells, and developmental disorders in the germline. How does the cell integrate biochemical and mechanical processes to ensure that its genetic material is equally distributed to daughter cells? While we have a nearly complete list of molecules essential to cell division, we know very little about the underlying mechanical interactions and principles. The Dumont Lab aims to understand how cells generate, detect, and respond to mechanical forces to accurately segregate their chromosomes, and how mechanical and biochemical information is integrated for cellular decision making.

Two macromolecular machines coordinate chromosome segregation: the μm-scale spindle moves chromosomes through its growing and shrinking microtubules, and the 100nm-scale kinetochore anchors chromosomes to spindle microtubules and regulates their segregation. How do these two machines precisely and robustly divide chromosomes, and how do their nm‐scale constituents work together to generate μm-scale movements?

Our work focuses on the basic requirements of accurate chromosome segregation: moving chromosomes, and moving them to the right places. How do shrinking and growing microtubule tips generate force to move chromosomes, and how do chromosomes hold on to such dynamic structures? Furthermore, how can the spindle be strong enough to oppose these forces, and yet dynamic enough to remodel itself as chromosomes move? Finally, how does the cell verify that chromosome copies are correctly attached to the spindle prior to segregating them, such that its genetic material will be equally distributed to daughter cells?

To address these questions, one must uncover how molecules, mechanics and cellular function relate to each other. We thus use an inter-disciplinary approach. We probe key players using cell and molecular tools, map how the cell’s machines are organized and designed using sub-pixel resolution imaging, and mechanically perturb cells by cutting their structures and poking them. Together, our work will build fundamental knowledge in how mechanical and chemical processes are integrated over cellular length scales, and in life processes that, if perturbed, cause disease.

Selected publications:

Dumont S, Salmon ED, Mitchison TJ. Deformations within moving kinetochores reveal different sites of active and passive force generation. Science 337, 355-358 (2012).

Dumont S, Mitchison TJ. Mechanical Forces in Mitosis. Book chapter in: Edward H. Egelman, editor: Comprehensive Biophysics, Vol 4, Molecular Motors and Motility, Yale E. Goldman, E. Michael Ostap. Oxford: Academic Press, pp. 298-320 (2012).

Dumont S. Chromosome Segregation: Spindle Mechanics Come to Life. Current Biology 21, R688-690 (2011).

Dumont S, Mitchison TJ. Force and length in the mitotic spindle. Current Biology 19, R749-R761 (2009).

Dumont S, Mitchison TJ. Compression regulates spindle length by a mechanochemical switch at the poles. Current Biology 19, 1086-1095 (2009).

Wühr M, Dumont S, Groen AC, Needleman DJ, Mitchison TJ. How does a millimeter-sized cell find its center? Cell Cycle 8, 1115-1121 (2009).

Wühr M, Chen Y, Dumont S, Groen AC, Needleman DJ, Salic A, Mitchison TJ. Evidence for an upper limit to mitotic spindle size. Current Biology 18, 1-6 (2008).

Cheng W*, Dumont S*, Tinoco I Jr, Bustamante C. NS3 helicase actively separates RNA strands and senses sequence barriers ahead of the opening fork. PNAS 104, 13954-13959 (2007). (*co-first author)

Dumont S*, Cheng W*, Serebrov V, Beran RK, Tinoco I Jr, Pyle AM, Bustamante C. RNA unwinding mechanism of HCV NS3 helicase and its coordination by ATP. Nature 439, 105-108 (2006). (*co-first author)

Onoa B*, Dumont S*, Liphardt J, Smith SB, Tinoco I Jr, Bustamante C. Identifying the kinetic barriers to mechanical unfolding of the T. thermophila ribozyme. Science 299, 1892-1895 (2003). (*co-first author)

Liphardt J, Dumont S, Smith SB, Tinoco I Jr, Bustamante C. Equilibrium information from nonequilibrium measurements in an experimental test of Jarzynski's equality. Science 296, 1832-1835 (2002).