Therapeutic 6-thio-deoxyguanosine inhibits telomere elongation in cancer cells by inducing a non-productive stalled telomerase complex

Samantha L Sanford¹, Mareike Badstübner², Michael Gerber¹, William Mannherz^{3

4

5}, Noah Lampl^{4

5}, Rachel Dannenberg⁶, Angela Hinchie^{7

8}, Matthew A Schaich^{1

9}, Sua Myong^{10

11}, Mark Hedglin⁶, Suneet Agarwal^{3

4

5}, Jonathan K Alder^{7

8}, Michael D Stone^{2

12}, Patricia L Opresko^{13

14

15}

Affiliations

¹ UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
² Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA, USA.
³ Division of Hematology/Oncology and Stem Cell Program, Boston Children's Hospital, Boston, MA, USA.
⁴ Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁵ Biological and Biomedical Sciences Program, Harvard/MIT MD-PhD Program, Harvard Stem Cell Institute, Harvard Initiative for RNA Medicine, and Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
⁶ Department of Chemistry, The Pennsylvania State University, University Park, PA, USA.
⁷ Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, PA, USA.
⁸ Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁹ Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁰ Program in Cell, Molecular, Developmental Biology and Biophysics, Johns Hopkins University, Baltimore, MD, USA.
¹¹ Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
¹² RNA Center, University of California Santa Cruz, Santa Cruz, CA, USA.
¹³ UPMC Hillman Cancer Center, Pittsburgh, PA, USA. plo4@pitt.edu.
¹⁴ Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. plo4@pitt.edu.
¹⁵ Department of Environmental and Occupational Health, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA. plo4@pitt.edu.

PMID: 41354720
DOI: 10.1038/s41467-025-66534-w

Free article

Therapeutic 6-thio-deoxyguanosine inhibits telomere elongation in cancer cells by inducing a non-productive stalled telomerase complex

Samantha L Sanford et al. Nat Commun. 2025.

Free article

. 2025 Dec 7.

doi: 10.1038/s41467-025-66534-w. Online ahead of print.

Authors

Affiliations

¹ UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
² Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA, USA.
³ Division of Hematology/Oncology and Stem Cell Program, Boston Children's Hospital, Boston, MA, USA.
⁴ Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁵ Biological and Biomedical Sciences Program, Harvard/MIT MD-PhD Program, Harvard Stem Cell Institute, Harvard Initiative for RNA Medicine, and Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
⁶ Department of Chemistry, The Pennsylvania State University, University Park, PA, USA.
⁷ Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, PA, USA.
⁸ Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁹ Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁰ Program in Cell, Molecular, Developmental Biology and Biophysics, Johns Hopkins University, Baltimore, MD, USA.
¹¹ Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
¹² RNA Center, University of California Santa Cruz, Santa Cruz, CA, USA.
¹³ UPMC Hillman Cancer Center, Pittsburgh, PA, USA. plo4@pitt.edu.
¹⁴ Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. plo4@pitt.edu.
¹⁵ Department of Environmental and Occupational Health, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA. plo4@pitt.edu.

PMID: 41354720
DOI: 10.1038/s41467-025-66534-w

Abstract

Most cancers upregulate the telomere lengthening enzyme telomerase to achieve unlimited cell division. How chemotherapeutic nucleoside 6-thio-2'-deoxyguanosine (6-thio-dG) targets telomerase to inhibit telomere maintenance in cancer cells and tumors was unclear. Here, we demonstrate that telomerase insertion of 6-thio-dGTP prevents synthesis of additional telomeric repeats but does not disrupt telomerase binding to telomeres. Specifically, 6-thio-dG inhibits telomere extension after telomerase translocates along its product DNA to reposition the template, inducing a non-productive complex rather than enzyme dissociation. Furthermore, we provide direct evidence that 6-thio-dG treatment inhibits telomere synthesis by telomerase in cancer cells. In agreement, telomerase-expressing cancer cells harboring critically short telomeres are more sensitive to 6-thio-dG and show a greater induction of telomere losses compared to cancer cells with long telomere reserves. Our studies reveal that telomere length and telomerase status determine 6-thio-dG sensitivity and uncover the molecular mechanism by which 6-thio-dG selectively inhibits telomerase synthesis of telomeric DNA.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

Update of

Chemotherapeutic 6-thio-2'-deoxyguanosine selectively targets and inhibits telomerase by inducing a non-productive telomere-bound telomerase complex.
Sanford SL, Badstübner M, Gerber M, Mannherz W, Lampl N, Dannenberg R, Hinchie A, Schaich MA, Myong S, Hedglin M, Agarwal S, Alder JK, Stone MD, Opresko PL. Sanford SL, et al. bioRxiv [Preprint]. 2025 Jun 27:2025.02.05.636339. doi: 10.1101/2025.02.05.636339. bioRxiv. 2025. Update in: Nat Commun. 2025 Dec 7. doi: 10.1038/s41467-025-66534-w. PMID: 39975053 Free PMC article. Updated. Preprint.

References

1. de Lange, T. Shelterin-mediated telomere protection. Annu. Rev. Genet. 52, 223–247 (2018).
1. d’Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003).
1. Jaskelioff, M. et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469, 102–106 (2011).
1. Takai, H., Smogorzewska, A. & de Lange, T. DNA damage foci at dysfunctional telomeres. Curr. Biol. 13, 1549–1556 (2003).
1. Shay, J. W. & Wright, W. E. Senescence and immortalization: role of telomeres and telomerase. Carcinogenesis 26, 867–874 (2005).

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Therapeutic 6-thio-deoxyguanosine inhibits telomere elongation in cancer cells by inducing a non-productive stalled telomerase complex

Affiliations

Therapeutic 6-thio-deoxyguanosine inhibits telomere elongation in cancer cells by inducing a non-productive stalled telomerase complex

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

Grants and funding

LinkOut - more resources

Full Text Sources