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 and 4 more
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
2 · The registry
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Samantha L SanfordUPMC Hillman Cancer Center, Pittsburgh, PA, USA.
Mareike BadstübnerDepartment of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA, USA.
Michael GerberUPMC Hillman Cancer Center, Pittsburgh, PA, USA.
William MannherzDivision of Hematology/Oncology and Stem Cell Program, Boston Children's Hospital, Boston, MA, USA.ORCID 0000-0003-4472-7394
Noah LamplPediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Rachel DannenbergDepartment of Chemistry, The Pennsylvania State University, University Park, PA, USA.
Angela HinchieDorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, PA, USA.
Matthew A SchaichUPMC Hillman Cancer Center, Pittsburgh, PA, USA.
Sua MyongProgram in Cell, Molecular, Developmental Biology and Biophysics, Johns Hopkins University, Baltimore, MD, USA.ORCID 0000-0001-9098-3423
Mark HedglinDepartment of Chemistry, The Pennsylvania State University, University Park, PA, USA.ORCID 0000-0003-2599-1691
Suneet AgarwalDivision of Hematology/Oncology and Stem Cell Program, Boston Children's Hospital, Boston, MA, USA.ORCID 0000-0003-4910-3118
Jonathan K AlderDorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, PA, USA.ORCID 0000-0003-3741-6512
Michael D StoneDepartment of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA, USA.ORCID 0000-0002-2060-4501
Patricia L OpreskoUPMC Hillman Cancer Center, Pittsburgh, PA, USA. plo4@pitt.edu.ORCID 0000-0002-6470-2189
Funding
VECTOR CORE FACILITYP30CA047904 · NCI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Jessie Nedrow · 1988 to 2026
$158.0M
Medical Scientist Training ProgramT32GM144273 · NIGMS · HARVARD MEDICAL SCHOOL · PI David Shumway Jones, Jacqueline A. Lees · 2022 to 2026
$14.7M
Supplement to Promote DiversityR35ES030396 · NIEHS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Patricia L Opresko · 2019 to 2026
$7.5M
Regulation of the telomerase RNA component in hematopoiesisR01DK107716 · NIDDK · BOSTON CHILDREN'S HOSPITAL · PI SUNEET AGARWAL · 2016 to 2026
$5.0M
Structure and dynamics of the Tetrahymena telomerase ribonucleoproteinR01GM095850 · NIGMS · UNIVERSITY OF CALIFORNIA SANTA CRUZ · PI STONE, MICHAEL D · 2011 to 2023
$4.4M
Mechanisms of Telomere-Mediated Lung DiseaseR01HL135062 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Jonathan K. Alder · 2018 to 2026
$4.1M
Roles of Telomeric Oxidative DNA Lesions in Telomere Length RegulationR01CA207342 · NCI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Sua Myong, Patricia L Opresko · 2017 to 2026
$3.7M
Deciphering the progression and regulation of human translesion DNA synthesisR35GM147238 · NIGMS · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · PI Mark Hedglin · 2022 to 2026
$2.0M
Structure and Dynamics of Telomeres and TelomeraseR35GM153235 · NIGMS · UNIVERSITY OF CALIFORNIA SANTA CRUZ · PI Michael D Stone · 2024 to 2026
$1.3M
Lumicks C-Trap Optical Tweezers with Confocal Fluorescence MicroscopeS10OD032158 · OD · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI VAN HOUTEN, BENNETT · 2023 to 2023
$552k
Investigating how chemotherapeutic thiopurines inhibit telomerase elongation of telomeresF32CA275287 · NCI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI SANFORD, SAMANTHA · 2023 to 2025
$226k
Control of Telomere Homeostasis by Nucleotide Metabolism in HematopoiesisF30DK135340 · NIDDK · HARVARD MEDICAL SCHOOL · PI William Mannherz · 2023 to 2026
$188k
Division of Cancer Prevention, National Cancer Institute (NCI Division of Cancer Prevention) F32CA275287NCI NIH HHS F32 CA275287NCI NIH HHS P30 CA047904NCI NIH HHS R01 CA207342NHLBI NIH HHS R01 HL135062NIDDK NIH HHS F30 DK135340NIDDK NIH HHS R01 DK107716NIEHS NIH HHS F32 ES034982NIEHS NIH HHS R35 ES030396NIGMS NIH HHS R01 GM095850NIGMS NIH HHS R35 GM147238NIGMS NIH HHS R35 GM153235NIGMS NIH HHS T32 GM144273NIH HHS S10 OD032158U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01CA207342U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS) R35ES030396U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) R01GM095850U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) R35GM153235
6 · The paper itself
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.
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.
Therapeutic 6-thio-deoxyguanosine inhibits telomere elongation in cancer cells by inducing a non-productive stalled telomerase complex. · full record | OpenQuestion