Aneuploidy, or an abnormal number of chromosomes, results from improper sister chromatid segregation. It is a hallmark of human cancers. Using a combination of experiments and computational
modeling, we seek to understand how cells ensure proper sister chromatid separation, as it has strong implications for the development of cancer therapeutics.
In the opening of our video, a circling bicyclist establishes the boundary of the nuclear membrane. Slinkies represent chromosomes located within the nucleus. Lastly, dancers wearing black and white
represent alpha and beta tubulin, the subunits that form the dynamic polymer structures called microtubules, located outside the nucleus. When the nuclear envelope breaks down (the bicyclist falls),
the chromosomes are available for microtubule capture.
During prometaphase, microtubules search for and capture sister chromatids as they dynamically polymerize (grow) and depolymerize (shorten). Normally, sister chromatids attach to microtubules
from opposite spindle poles (achieve bi-orientation), which causes tension between sisters. If both sister chromatids attach to microtubules from the same pole (lack of tension) the daughter cells will gain or lose whole chromosomes and be aneuploid. Aurora kinases (pink dancers) come to the rescue by phosphorylating their substrates and forcing detachment of one sister, giving that sister another chance to obtain proper attachments. I am developing a computational model to answer the following question: if lack of tension causes phosphorylation and detachment, how will reattachment occur as long as the substrates are phosphorylated?
During metaphase, chromosomes align at the spindle equator. In the budding yeast spindle, the motor protein kinesin-5 facilitates congression by promoting disassembly of long kinetochore microtubules (Gardner, Cell, 2008). I am using fluorescence microscopy to study metaphase in various species to determine if this is a ubiquitous role for kinesin-5 homologs or budding yeast specific. In our dance, microtubules depolymerize with increased microtubule length.
Finally, when congression is complete, cohesion is lost between sister chromatids, they begin to move to opposite spindle poles in anaphase…then telophase occurs…then cytokinesis…then, here come two more bicyclists!
Again, in order to prevent aneuploidy,
Sister chromatids: You gotta keep ‘em separated!
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