Chemical Biology of Cell Division

The Chemical Biology of Cell Division research unit focuses on: 1) elucidating the molecular mechanisms by which kinesin motors and other microtubule-associated proteins contribute to mitotic spindle assembly, and 2) developing small molecule chemical tools that can be used in biomedical research and potentially as anti-cancer chemotherapeutics.

The assembly of a bipolar, microtubule-based machine called the mitotic spindle is essential for chromosome segregation during cell division. Inhibition of this process blocks cell cycle progression and is an effective strategy to treat cancer. Motor proteins in the kinesin superfamily play important roles in orchestrating spindle formation. Their ability to directly regulate microtubule organization and polymerization dynamics places them in a new class of chemotherapeutic targets.

We use a multi-disciplinary approach that combines protein biochemistry, cell biology and high resolution microscopy to study spindle formation in cultured vertebrate cells and in in vitro reconstitution assays. In the figure shown below, we reconstituted spindle assembly in the Xenopus egg extract system.

Figure 1. Spindle assembly in Xenopus egg extract. (a) Bipolar spindle forms around DNA-coated beads (to mimic chromosomes) in the presence of the tetrameric kinesin-5 motor Eg5, a protein required for spindle assembly. (b) In contrast, Eg5-depletion leads to the formation of a monopolar spindle structure– phenocopies loss of function of kinesin-5 in cells. (c) Addition of recombinant wildtype Eg5 or Eg5-GFP (shown here) rescues spindle bipolarity.

Figure 2. Motile activity of Eg5-GFP at single-molecule resolution. A time-lapse movie of tetrameric Eg5-GFP (green) moving on X-Rhodamine-labeled microtubules (Red) immobilized on a coverslip.

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