Hsp90 Inhibitors Gendanamycin and Novobiocin Inhbit Telomerase (2013)

Undergraduates: Yishu Wang, Lauren Wagner

Faculty Advisor: Michael Jarstfer
Department: Chemistry

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Telomeres are DNA sequences at the ends of chromosomes that protect them from degradation, fusion, and recombination. In somatic cells, telomeres shorten with each cell division, eventually signaling for cell death. However, cancer cells can up-regulate telomerase, a ribonucleoprotein complex, this is involved in the addition of six nucleotide repeats to the end of the chromosomes which lengthens them telomeres and allowing cells to live longer and continue prliferating. The telomerase complex is composed of the telomerase reverse transcriptase (TERT), telomerase RNA, and a variety of chaperone proteins, one of which is heat shock protein 90 (HSp90). Previous studies in our lab have suggested that Hsp90 plays a role in assembling mature telomerase complexes and that the Hsp90 inhibitors novobiocin and geldanamycin can inhibit telomerase activity in reticulocyte lysates. Using telomerase cell extracts and purified telomerase complexes isolated from cells over-expressing telomerase, we have once again shown that both of these compounds can decrease telomerase activity in a dose-dependent manner. Interestingly though, recent cryo-EM data of active telomerase complexes demonstrates that Hsp90 is not included in the telomerase holoenzyme suggesting that novobiocin and geldanamycin may inhibit telomerase activity through a different mechanism.