Making the Cut: The Chemical Biology of Cytokinesis

Abstract

Cytokinesis is the last step in the cell cycle, where daughter cells finally separate. Cytokinesis is precisely regulated in both time and space to ensure that each daughter cell receives an equal share of DNA and other cellular materials. Successful completion of cytokinesis, with the cleavage furrow exactly bisecting the axis of chromosome segregation, involves the coordinated action of the cytoskeleton, cell cycle and membrane machineries of cells (1). Chemical biology approaches have been used very successfully to study the mechanism of cytokinesis. In this review, we will discuss the use of small molecule probes to perturb cytokinesis as well as on role that naturally occurring small molecule metabolites such as lipids play during cytokinesis. The mechanism of cytokinesisCytokinesis occurs immediately after mitosis, the division of DNA. The mechanism of cytokinesis has been reviewed in detail elsewhere (1-3). Here, we will briefly introduce key steps to provide context for this review. During mitosis, chromosomes line up in a metaphase plate at the center of the mitotic spindle. As the chromosomes are dividing, a dramatic and poorly understood rearrangement of microtubules takes place and a contractile ring begins to assemble (Figure 1). Contact of the cellular cortex (and plasma membrane?) with microtubule structures is essential for the correct positioning of the contractile ring. Several possible mechanisms have been proposed, although recent studies suggest that multiple mechanisms may occur simultaneously (2,4,5). There are several main signaling pathways, for example those centered around Aurora B and Polo kinases and the small GTPase Rho, that operate and are essential throughout cytokinesis (1). As the location of the cleavage furrow is being specified, the contractile ring begins to assemble. The temporal sequence of protein recruitment to the ring is a significant, but poorly understood mechanistic feature of early cytokinesis. The complete composition of the ring is not known, but the plasma membrane, actin, myosin II and Anillin are clearly important (Figure 1) (6-8). It is not known how the contractile ring is linked to the plasma membrane during ring assembly or ingression. The contractile ring then ingresses, with actin and myosin providing much of the mechanical force (1). We have partial information for the stages of cytokinesis described so far, but the last step, called completion or abscission, remains the least understood. At the end of ingression, a small structure, the midbody, forms. Severing between the daughter cells, which has to be very carefully controlled to avoid the generation of a hole in the cell, occurs in this structure (9). Targeted vesicle transport is thought to play a role both during contractile ring ingression and in generating a membrane barrier that seals the daughter cells during severing (10)(11)(12)(13)(14)(15) (16,17). Insights into the timing of contractile ring assembly during cytokinesis have come from studies in S. pombe (18). Since fungi have many organis...

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