Centromere Mechanical Maturation And Mitotic Fidelity During Mammalian Cell Mitosis
2018-05
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Centromere Mechanical Maturation And Mitotic Fidelity During Mammalian Cell Mitosis
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2018-05
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Mitotic fidelity, a cell’s ability to accurately and reliably replicate its genome during cell division, is frequently disrupted in cancer and may significantly impact disease course by selecting for tumor promoting mutations. Thus, the ability to target the mitotic fidelity of cancer cells could be an important therapeutic approach to reducing cancer-associated morbidity and mortality. The mechanical function of the centromere, a specialized region of the chromosome that interacts with the mitotic spindle, is likely to be intimately connected to mitotic fidelity. During mitosis, mechanical tension develops across the centromere as a result of spindle-based forces. This is important because tension-based force signaling may play a critical role in preventing chromosome segregation errors during mitosis that result from incorrect attachments between the mitotic spindle and the chromosomes. However, the role of the centromere in establishing the magnitude and cell-cycle specificity of tension signaling, and its effect on chromosome segregation outcomes, remains unknown. Further, centromere mechanics have not been quantitatively characterized in vivo for mitotic human cells, and so the effect of disease states such as cancer on their function is largely unknown. We combined quantitative, biophysical microscopy with computational analysis in order to elucidate the mechanics of the centromere in unperturbed, mitotic mammalian cells. Our approach revealed that the mechanics of the mammalian centromere mature with a signature pattern during mitotic progression. Importantly, this maturation leads to amplified centromere tension specifically at metaphase. Thus, centromere mechanical maturation provides a positive feedback mechanism to increase the centromere’s tension signal during mitotic progression. Further, we found that a disruption in centromere mechanical maturation led to diminished tension at metaphase in cancer cells, and that this disruption increased in severity with increasing chromosome number. Strikingly, in cells with disrupted centromere mechanical maturation, the frequency of tension-based chromosome attachment errors was elevated, and these errors were more likely to persist into segregation defects at telophase. Thus, we reveal a novel role for the centromere in regulating tension during mitosis, and demonstrate a direct link between aneuploidy, centromere mechanics, and chromosome mis-segregation.
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University of Minnesota Ph.D. dissertation.May 2018. Major: Biomedical Informatics and Computational Biology. Advisor: Melissa Gardner. 1 computer file (PDF); xi, 175 pages.
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Harasymiw, Lauren. (2018). Centromere Mechanical Maturation And Mitotic Fidelity During Mammalian Cell Mitosis. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/215177.
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