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David Odde
University of Minnesota

Stochastic Mechanics of the Mitotic Spindle

Chromosome segregation is mediated by the dynamic interplay of microtubule assembly and molecular motors, which act in concert to stretch sister chromosome pairs. Failure to develop chromosome tension is characteristic of improperly attached chromosomes, and is sensed by checkpoint and error correction mechanisms to prevent chromosome missegregation. How do chromosomes develop proper tension? Through integration of quantitative fluorescence microscopy and stochastic computer simulation of the dynamics of kinetochore microtubules (kMTs) in budding yeast, we have identified two primary influences on kMT plus end assembly. First, net assembly depends on kMT plus end position within the spindle, such that assembly is favorable near the poles and unfavorable near the equator. By itself, this situation establishes a "barrier" to assembly that tends to prevent MT plus ends from crossing the equator, thereby establishing the rudiments of a bipolar spindle with sister plus ends generally constrained to their respective half-spindles. Second, increased tension between sister plus ends, mediated via elastic chromatin stretching, promotes net assembly. Together with the spatial gradient effect, tension-dependent assembly serves as an error-correcting mechanism that promotes kMT disassembly in the rare instances when a plus end crosses the equator. In this case, tension on the chromosome is low, which leads to kMT disassembly. Finally, since chromosome mechanical properties are important to the tension-dependent assembly, and spindle mechanics generally, we developed a model for chromatin stretching in budding yeast. We predict that the chromatin is sufficiently stretched so that nucleosomal release is driven by the tension. We developed a stochastic simulation of chromatin stretching that accounts for nucleosomal release, and find that a stochastic stress-strain relationship can be established.

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