Telomeres cap and protect the ends of all human chromosomes. In healthy adult tissue, telomeres shorten with each round of cell division as part of the normal aging process. This mechanism limits human cells to a finite number of cell divisions before induction of programmed cell death and therefore serves as a tumor suppressor. In cancer cells, however, an enzyme called telomerase is upregulated to nullify the limited number of cell divisions. As such, cancer cells are capable of infinite division, which allows proliferation of ~90% of all pancreatic cancers. Due to this unique and critical role in cancer biology, telomerase provides a novel target for innovative therapeutics. The purpose of the present proposal is to explore a completely new mechanism toward using telomerase as an anti-cancer target. In our approach, we will design non-native nucleotide analogs to be preferentially and selectively incorporated by telomerase into telomere DNA. Once incorporated, the non-native nucleotides should abrogate binding of essential telomere-end binding proteins such as the Protection of Telomeres 1 (POT1), which is highly specific for telomere DNA sequence. Abrogation of POT1 binding induces cell death through a cascade of DNA damage events. The cell- killing potential of these non-native nucleotide compounds will be validated by measuring their potency and selectivity against telomerase-positive, pancreatic cancer cell lines. We predict that our strategy will provide a selective mechanism to potentially treat human pancreatic cancer.
Telomerase is a unique enzyme that is present in pancreatic carcinoma cells, but undetectable in healthy adult tissue. The purpose of the present proposal is to exploit this unique trait and target telomerase selectively in cancer cells. To do so, an approach using telomerase to selectively insert toxic compounds into the DNA of tumors will be explored.
|Choi, Jung-Suk; Berdis, Anthony J (2016) Visualizing nucleic acid metabolism using non-natural nucleosides and nucleotide analogs. Biochim Biophys Acta 1864:165-76|
|Scotland, Michelle K; Heltzel, Justin M H; Kath, James E et al. (2015) A Genetic Selection for dinB Mutants Reveals an Interaction between DNA Polymerase IV and the Replicative Polymerase That Is Required for Translesion Synthesis. PLoS Genet 11:e1005507|
|Rajavel, Malligarjunan; Mullins, Michael R; Taylor, Derek J (2014) Multiple facets of TPP1 in telomere maintenance. Biochim Biophys Acta 1844:1550-9|