Telomere maintenance as a therapeutic target

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Creator

Henderson, Rachel Anne
- Affiliation: Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry

Abstract

Telomere maintenance is essential for long term cell survival, with two mechanisms contributing to telomere maintenance: telomeric DNA elongation by telomerase and a capping mechanism contributing to telomere stability. Several therapeutic approaches targeting telomeres have been explored but many rely on a lag period of telomere degradation before anti-proliferation occurs. Two strategies presented here aim to disrupt telomere maintenance while eliminating the lag period. First, telomerase was inhibited using antisense oligonucleotides targeting its RNA subunit (hTR). The goal of this study was to both prevent active holoenzyme assembly and induce degradation of the protein subunit (hTERT) thought to be associated with anti-apoptotic activity. Additionally, a fluorescence polarization assay was designed for the identification of small molecule inhibitors of telomeric repeat binding factor 2 (TRF2), a key capping protein involved in prevention of chromosomal end fusions and ultimately cellular apoptosis.

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