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    Mechanism of DNA damage responses induced by exposure to an oligonucleotide homologous to the telomere overhang in melanoma

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    Main Article (1.615Mb)
    Date
    2013-06
    Author
    Wojdyla, Luke
    Puri, Neelu
    Pitman, Ryan T.
    Publisher
    Impact Journals
    Metadata
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    Abstract
    T-oligo, an 11-base oligonucleotide homologous to the 3’-telomeric overhang, is a novel, potent therapeutic modality in melanoma and multiple other tumor types. T-oligo is proposed to function in a manner similar to experimental disruption of the telomere overhang and induces DNA damage responses including apoptosis, differentiation and senescence. However, important components involved in T-oligo induced responses are not defined, particularly the role of p53, TRF1 and TRF2 in mediating the T-oligo induced responses. In MU, PM-WK, and MM-MC melanoma cells, exposure to T-oligo upregulates p53 expression and phosphorylation, resulting in cellular differentiation and activation of a caspase-mediated apoptotic cascade. However, siRNA-mediated knockdown of p53 completely blocks T-oligo induced differentiation and significantly decreases apoptosis, suggesting that p53 is an important mediator of T-oligo induced responses. In addition, we characterized the roles of telomere binding proteins, TRF1, TRF2, and tankyrase-1, in T-oligo induced damage responses. We demonstrate that tankyrase-1 activity is required for initiation of T-oligo induced damage responses including p53 phosphorylation and reduction of cellular proliferation. These results highlight TRF1, TRF2, tankyrase-1 and p53 as important elements in T-oligo mediated responses and suggest new avenues for research into T-oligo’s mechanism of action.
    Subject
    T-oligo
    Tankyrase
    Telomere
    TRF1
    melanoma
    Type
    Article
    Date available in INDIGO
    2014-02-10T17:48:03Z
    URI
    http://hdl.handle.net/10027/11151
    Collections
    • Publications - Biomedical Sciences

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