Mechanism of DNA damage responses induced by exposure to an oligonucleotide homologous to the telomere overhang in melanoma
Metrics: PDF 1806 views | HTML 2383 views | ?
Ryan T Pitman1,* Luke Wojdyla1, Neelu Puri1,*
1 Department of Biomedical Sciences, University of Illinois College of Medicine, Rockford, Illinois
* These authors contributed equally to this study
Neelu Puri, email:
Keywords: T-oligo, Tankyrase, TRF1, telomere, p53, melanoma
Received: May 21, 2013 Accepted: June 1, 2013 Published: June 3, 2013
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.