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THE MULTIFACETED ROLE OF EXONUCLEASE 1 IN DNA REPAIR AND ADULT STEM CELL POPULATIONS

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2014, Doctor of Philosophy, Case Western Reserve University, Pharmacology.
The DNA damage response is composed of multiple signaling and repair pathways which together constitute an important tool cells utilize to preserve genomic stability. Repair pathways have shown to be critical in many cell types, including in human cancers where upregulation of DNA repair is believed to contribute to therapy resistance. In normal human development it is vital to stem cell populations, including in the hematopoietic system, where maintenance of genomic stability is necessary for development and normal immune function. The precise proteins and pathways responsible for maintaining cellular damage responses are often cell type specific, and identification of critical repair enzymes continues to yield promising therapeutic targets for a plethora of human conditions. The 5’->3’ nuclease Exonuclease 1 (Exo1) has been implicated in several cellular processes including DNA mismatch and double strand break repair. Its upregulation has been characterized in human cancers of the breast, lung, colon, bladder and others. Here we examine the role of Exo1 in multiple contexts, including in hematopoietic stem cells (HSC), where we describe Exo1 loss in the HSC damage response both in quiescent and active settings. We demonstrate that while Exo1 and homologous recombination (HR) are dispensable for HSCs at steady state, stress induced cell cycle entry results in an HSC reliance on Exo1 mediated HR. We also explore the importance of DNA repair pathways and Exo1 in human lung cancer stem cells using the CD133 marker, and characterize the potential for Exo1 silencing as a cancer stem cell specific therapy. We find that upon prior exposure to double-strand break therapy, CD133+ cells are activated and rely on multiple DNA repair proteins including Exo1, and that this reliance contributes to radiation resistance. Finally we mechanistically describe the role of Exo1 in DNA Mismatch Repair (MMR) and identify a compensatory Exo1 independent pathway that cells adopt to minimize genomic instability involving the additional 5’-->3’ nucleases Artemis, Fan1, and Mre11. Collectively our findings provide deeper insight into the DNA repair dependence of multiple stem cell populations and characterize the importance of Exonuclease 1 both in stem cell maintenance and as a potential therapeutic target.
Stanton Gerson (Advisor)
Derek Taylor (Committee Chair)
Scott Welford (Committee Member)
Guangbin Luo (Committee Member)
Anthony Berdis (Committee Member)
168 p.

Recommended Citations

Citations

  • Desai, A. (2014). THE MULTIFACETED ROLE OF EXONUCLEASE 1 IN DNA REPAIR AND ADULT STEM CELL POPULATIONS [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1390400837

    APA Style (7th edition)

  • Desai, Amar. THE MULTIFACETED ROLE OF EXONUCLEASE 1 IN DNA REPAIR AND ADULT STEM CELL POPULATIONS . 2014. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1390400837.

    MLA Style (8th edition)

  • Desai, Amar. "THE MULTIFACETED ROLE OF EXONUCLEASE 1 IN DNA REPAIR AND ADULT STEM CELL POPULATIONS ." Doctoral dissertation, Case Western Reserve University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1390400837

    Chicago Manual of Style (17th edition)