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

Sep 24, 2026

Therapeutic 6-thio-2’-deoxyguanosine targets telomerase maintenance in cancer cells by enabling insertion of 6-thio-dGTP into telomeres. The study shows that this blocks synthesis of additional telomeric repeats while preserving telomerase binding. After telomerase translocates along product DNA and repositions its template, 6-thio-dG induces a non-productive stalled complex rather than dissociation. Direct cell evidence links THIO treatment to reduced telomere synthesis, and critically short-telomere cancer cells exhibit higher sensitivity and greater telomere losses than cells with long telomere reserves.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages19

Reading Time48 min

AccessFree to download

Background

Telomeres and telomerase in cancer

Telomere dysfunction and DNA damage response

Mechanism and experimental findings

THIO/6-thio-dG blocks telomeric repeat synthesis

Telomerase binding preserved but synthesis stalls

Cellular sensitivity depends on telomere length

Article [https://doi.org/10.1038/s41467-025-66534-w](https://doi.org/10.1038/s41467-025-66534-w) Therapeutic 6-thio-deoxyguanosine inhibits telomere elongation in cancer cells by inducing a non-productive stalled telomerase complex Received: 24 February 2025 | Accepted: 10 November 2025 | | --- | | | | Check for updates | Samantha L. Sanford1, Mareike Badstübner2, Michael Gerber1, William Mannherz 3,4,5, Noah Lampl4,5, Rachel Dannenberg6, Angela Hinchie7,8, Matthew A. Schaich1,9, Sua Myong 10,11, Mark Hedglin 6, Suneet Agarwal 3,4,5, Jonathan K. Alder 7,8, Michael D. Stone 2,12 & Patricia L. Opresko 1,9,13 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. Telomeres are nucleoprotein DNA structures that protect the ends of linear chromosomes and are essential for genome stability and cellular proliferation. Human telomeres consist of approximately 10-15 kilobases (kb) of tandem double-stranded GGTTAG repeats, a 3’-singlestranded (ss) G-rich overhang ranging from 50 to 200 nt, and a complex of six proteins that are collectively called Shelterin1. Telomeres progressively shorten with each cell division, and extensive telomere shortening or losses trigger cell senescence and aging-related pathologies2,3. Critically short telomeres are falsely recognized as chromosome breaks, thereby activating an ATM and/or ATR kinasemediated DNA damage response (DDR), leading to p53 activation1. Dysfunctional telomeres are indicated by the localization of DDR factors 53BP1 or phosphorylated histone H2AX to telomeres, termed TIFor DDR+ telomeres2,4. In this context, dysfunctional telomeres serve asan initial barrier to tumorigenesis. However, when p53 pathways are compromised or mutated, cells may bypass senescence and continue to divide with critically short telomeres5. During this period, DNA double-strand break repair (DSBR) mechanisms generate chromosome end-to-end fusions, thereby promoting chromosomal instability that kills most cells but drives malignant transformation in those that survive6,7. The surviving cells either activate the recombination-based alternative lengthening of telomeres (ALT) pathway or, in most cases, A full list of afﬁliations appears at the end of the paper. e-mail: [plo4@pitt.edu](plo4@pitt.edu) upregulate telomerase to maintain telomeres to enable unlimited cell proliferation8,9. Telomerase has been identiﬁed as a target for cancer therapy since it is expressed in over 85% of cancers10, and most normal somatic cells lack telomerase3,11. Cancer cells typically undergo extensive telomere shortening before telomerase upregulation and generally maintain their telomeres at shorter lengths than normal cells8,12. Thus, transient telomerase inhibition has the potential to deplete telomeres more rapidly in highly proliferating cancer cells with short telomeres while reducing the risk for ext

FAQs

How does therapeutic 6-thio-deoxyguanosine affect telomerase function?

Telomerase insertion of 6-thio-dGTP prevents synthesis of further telomeric repeats while not disrupting telomerase binding to telomeres.

What mechanism explains why telomerase does not extend telomeres under 6-thio-dG treatment?

After telomerase translocates along product DNA to reposition the template, 6-thio-dG induces a non-productive stalled telomerase complex instead of enzyme dissociation.

Why are cancer cells with critically short telomeres more sensitive to 6-thio-dG?

Telomere length and telomerase status determine sensitivity, and critically short telomere cells show greater induction of telomere losses than long-telomere reserve cells.

Sep 24, 2026

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