{"doi":"10.1101/2025.02.05.636339","title":"Chemotherapeutic 6-thio-2’-deoxyguanosine selectively targets and inhibits telomerase by inducing a non-productive telomere-bound telomerase complex","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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":557295,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9564,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1134059,"name":"Mareike Badstübner","orcid":"0000-0003-0093-0788","position":1,"is_corresponding":false},{"id":501726,"name":"Michael H. Gerber","orcid":"0000-0001-5283-7417","position":2,"is_corresponding":false},{"id":1023142,"name":"William Mannherz","orcid":"0000-0003-4472-7394","position":3,"is_corresponding":false},{"id":1352888,"name":"Noah Lampl","orcid":null,"position":4,"is_corresponding":false},{"id":956251,"name":"Rachel L. Dannenberg","orcid":null,"position":5,"is_corresponding":false},{"id":871099,"name":"Angela M. Hinchie","orcid":"0000-0002-4544-4735","position":6,"is_corresponding":false},{"id":1457562,"name":"Matthew A Schaich","orcid":null,"position":7,"is_corresponding":false},{"id":284455,"name":"Sua Myong","orcid":"0000-0001-9098-3423","position":8,"is_corresponding":false},{"id":415429,"name":"Mark Hedglin","orcid":"0000-0003-2599-1691","position":9,"is_corresponding":false},{"id":70610,"name":"Suneet Agarwal","orcid":"0000-0003-4910-3118","position":10,"is_corresponding":false},{"id":58179,"name":"Jonathan K. Alder","orcid":"0000-0003-3741-6512","position":11,"is_corresponding":false},{"id":403975,"name":"Michael D. Stone","orcid":"0000-0002-2060-4501","position":12,"is_corresponding":false},{"id":323491,"name":"Patricia L. Opresko","orcid":"0000-0002-6470-2189","position":13,"is_corresponding":false},{"id":323488,"name":"Samantha L. Sanford","orcid":"0000-0002-6517-3557","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:17.435961Z","pmid":"39975053","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}