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

• Published in: Cell reports (Cambridge) Vol. 23; no. 10; pp. 3031 - 3041
• Main Authors: Zeng, Xuehuo, Hernandez-Sanchez, Wilnelly, Xu, Mengyuan, Whited, Tawna L., Baus, Diane, Zhang, Junran, Berdis, Anthony J., Taylor, Derek J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.06.2018
• Subjects: 5-fluoro-2'-deoxyuridine; Aminopeptidases - metabolism; Cell Death; Cell Line, Tumor; Deoxyuridine - analogs & derivatives; Deoxyuridine - metabolism; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - metabolism; DNA - metabolism; DNA Damage; floxuridine; Gene Silencing; HEK293 Cells; Humans; Models, Biological; Neoplasms - enzymology; Neoplasms - pathology; Nuclear Proteins - metabolism; Nucleosides - administration & dosage; POT1; Protein Binding; Pyrimidines - metabolism; RNA, Small Interfering - metabolism; Serine Proteases - metabolism; telomerase; Telomerase - metabolism; telomere; Telomere - metabolism; Telomere-Binding Proteins - metabolism; Thymidine - metabolism; POT1; telomerase; 5-fluoro-2'-deoxyuridine; floxuridine; DNA damage; telomere
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.05.020

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. [Display omitted] •Several nucleotide analogs, including 5-FdU, are effective substrates for telomerase•5-FdU induces apoptotic cell death in a telomerase-dependent manner•5-FdUTP reduces the binding affinity of POT1-TPP1 to telomere DNA•5-FdU-induced telomeric DNA damage results in activation of RPA, Chk1, and p53 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.