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The Role of the Human DEK Oncogene in the Regulation of DNA Damage Response and Repair

Kavanaugh, Gina M.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1305893047

Abstract Details

2011, PhD, University of Cincinnati, Medicine: Cell and Molecular Biology.
Altered chromatin integrity and improper DNA damage repair are commonly associated with the formation and progression of human cancers. Here, we investigate the contribution of the DEK oncogene – elevated in numerous human cancers – to DNA damage repair and chromatin stability. Initially, studies examining the effect of DEK loss demonstrated an accumulation of low levels of DNA damage markers in human cancer cells and xenografts, suggesting a deficiency in DNA damage repair. Importantly, DEK depletion led to alterations in DNA damage kinase response pathways. ATM pathway activation was increased, accounting for the elevated levels of H2AX phosphorylation observed in DEK deficient cells. Alternatively, DNA-PK phosphorylation and kinase activity were reduced with DEK loss. Similar DNA damage responses were observed in primary Dek knockout mouse embryonic fibroblasts (MEFs), along with increased levels of DNA damage and exaggerated induction of senescence in response to genotoxic stress. Importantly, Dek knockout MEFs exhibited distinct defects in non-homologous end-joining (NHEJ), micro-homology mediated end-joining (MMEJ), and homologous recombination (HR) repair when compared to their wild type counterparts. Notably, DEK-depleted Hela cells exhibited reduced levels of histone H2B ubiquitination. Histone modifications play an important role in genome topology and DNA damage repair. Additionally, H2B ubiquitination was recently reported to be required for the recruitment of NHEJ and HR components. We therefore hypothesize that DEK plays a role upstream of the DNA damage response as a regulator of chromatin stability and topology. Future studies concentrating on the contribution of DEK to genome integrity may reveal possible molecular DEK targets for the development of cancer therapeutics.
Susanne Wells, PhD (Committee Chair)
Paul Andreassen, PhD (Committee Member)
John Bissler, MD (Committee Member)
Karl Matlin, PhD (Committee Member)
Shao-Chun Wang, PhD (Committee Member)
Yi Zheng, PhD (Committee Member)
92 p.
Molecular Biology
DEK; DNA-PK; NHEJ; DNA damage repair; histone modification

Recommended Citations

Citations

  • Kavanaugh, G. M. (2011). The Role of the Human DEK Oncogene in the Regulation of DNA Damage Response and Repair [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1305893047

    APA Style (7th edition)

  • Kavanaugh, Gina. The Role of the Human DEK Oncogene in the Regulation of DNA Damage Response and Repair. 2011. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1305893047.

    MLA Style (8th edition)

  • Kavanaugh, Gina. "The Role of the Human DEK Oncogene in the Regulation of DNA Damage Response and Repair." Doctoral dissertation, University of Cincinnati, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1305893047

    Chicago Manual of Style (17th edition)

ucin1305893047
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© 2011, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.