Therapeutic 6-thio-deoxyguanosine inhibits telomere elongation in cancer cells by inducing a non-productive stalled telomerase complex
- Samantha L. Sanford
- Mareike Badstübner
- Michael Gerber
- William Mannherz
- Noah Lampl
- Rachel Dannenberg
- Angela Hinchie
- Matthew A. Schaich
- Sua Myong
- Mark Hedglin
- Suneet Agarwal
- Jonathan K. Alder
- Michael D. Stone
- Patricia L. Opresko
2025-12-07
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.