Symplekin and Transforming Acidic Coiled-Coil Containing Protein 3 Support the Cancer Cell Mitotic Spindle Public Deposited

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  • March 21, 2019
Creator
  • Cappell, Kathryn
    • Affiliation: School of Medicine, Department of Pharmacology
Abstract
  • An increased rate of proliferation in cancer cells, combined with abnormalities in spindle architecture, places tumors under increased mitotic stress. Previously, our laboratory performed a genome-wide paclitaxel chemosensitizer screen to identify genes whose depletion sensitizes non-small cell lung cancer (NSCLC) cells to mitotic stress induced by paclitaxel treatment. This screen uncovered a cohort of genes that are required for viability only in the presence of paclitaxel. Two genes uncovered in this screen were the polyadenylation scaffold symplekin and the gametogenic protein transforming acidic coiled-coil containing protein 3 (TACC3). Herein, we examine the impact of polyadenylation and gametogenesis on the tumor cell mitotic spindle. First, we demonstrate that depletion of SYMPK and other polyadenylation components sensitizes many NSCLC cells, but not normal immortalized lines, to paclitaxel by inducing mitotic errors and leading to abnormal mitotic progression. Second, we demonstrate that multiple gametogenic genes are required for normal microtubule dynamics and mitotic spindle formation in the presence of paclitaxel. Additionally, we show that the gametogenic protein TACC3 is uniquely required for mitosis only in transformed cell lines but not normal immortalized cell lines and that this unique dependency can be targeted in vitro with a small molecule. These studies reveal an unanticipated dependence of the cancer cell mitotic spindle on polyadenylation and gametogenic genes. We propose that, faced with mitotic stress, cancer cells develop conditional dependencies on processes such as polyadenylation that occur in all cells and emergent dependencies on gametogenic genes that are overexpressed in tumor cells.
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  • In Copyright
Advisor
  • Whitehurst, Angelique
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill
Graduation year
  • 2011
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