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    ZSCAN4: A Novel Regulator of Telomere Length in Cancer

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    Author
    Meltzer, W. Alex
    0000-0003-1175-8055
    Advisor
    Zalzman, Michal
    Date
    2017
    Type
    dissertation
    
    Metadata
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    Abstract
    Replicative immortality is facilitated by telomere maintenance through activating telomerase or by mechanisms collectively called alternative lengthening of telomeres (ALT). Zscan4c regulates telomere length of mouse embryonic stem cells, however, the activity of the human ZSCAN4 and its involvement in cancer is currently unknown. In this work, we describe for the first time the function and mechanism of ZSCAN4 in human cancer. We demonstrate that ZSCAN4 is dysregulated in a variety of cancers, and that ZSCAN4 is required to maintain both culture lifespan in vitro as well as cancer tumor growth in vivo. We further show that ZSCAN4 preferably binds to short telomeres and in conjunction with the telomeric recombination machinery MRE11A and RAD50 forms a complex on the telomere DNA-RNA hybrids. Loss of ZSCAN4 results in gradual telomere shortening which triggers an induction of growth arrest and replicative senescence. Consistently, ZSCAN4 induction increases DNA-RNA hybrids, facilitates telomere recombination events and consequently, telomere extension. Remarkably, we show that ZSCAN4 activates telomere extension irrespective of both telomerase as well as the canonical ALT pathway in cancer cells. Collectively, our work demonstrates a pivotal role for ZSCAN4 in the preservation of cancer replicative lifespan. This work provides the foundation for new approaches to cancer therapies.
    Description
    University of Maryland, Baltimore. Biochemistry. Ph.D. 2017
    Keyword
    ALT
    ZSCAN4
    Cancer
    Neoplasms
    Telomerase
    Telomere
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/7360
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    Theses and Dissertations All Schools
    Theses and Dissertations School of Medicine

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