Administration of a Nucleoside Analog Promotes Cancer Cell Death in a Telomerase-Dependent Manner

Telomerase, the end-replication enzyme, is reactivated in malignant cancers to drive cellular immortality. While this distinction makes telomerase an attractive target for anti-cancer therapies, most approaches for inhibiting its activity have been clinically ineffective. As opposed to inhibiting telomerase, we use its activity to selectively promote cytotoxicity in cancer cells. We show that several nucleotide analogs, including 5-fluoro-2′-deoxyuridine (5-FdU) triphosphate, are effectively incorporated by telomerase into a telomere DNA product. Administration of 5-FdU results in an increased number of telomere-induced foci, impedes binding of telomere proteins, activates the ATR-related DNA-damage response, and promotes cell death in a telomerase-dependent manner. Collectively, our data indicate that telomerase activity can be exploited as a putative anti-cancer strategy. Telomerase is an attractive target for anti-cancer therapies. Zeng et al. show that several nucleotide analogs, including 5-fluoro-2′-deoxyuridine (5-FdU), are effectively incorporated by telomerase to induce dysfunctional telomeres that activate the ATR-related DNA-damage response, resulting in cancer cell death in a telomerase-dependent manner.