{"doi":"10.1101/2023.02.10.528023","title":"Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance","abstract":"Telomere length maintenance is essential for cellular immortalization and tumorigenesis. 5% - 10% of human cancers rely on a recombination-based mechanism termed alternative lengthening of telomeres (ALT) to sustain their replicative immortality, yet there are currently no targeted therapies. Through CRISPR/Cas9-based genetic screens in an ALT-immortalized isogenic cellular model, here we identify histone lysine demethylase KDM2A as a molecular vulnerability selectively for cells contingent on ALT-dependent telomere maintenance. Mechanistically, we demonstrate that KDM2A is required for dissolution of the ALT-specific telomere clusters following homology-directed telomere DNA synthesis. We show that KDM2A promotes de-clustering of ALT multitelomeres through facilitating isopeptidase SENP6-mediated SUMO deconjugation at telomeres. Inactivation of KDM2A or SENP6 impairs post-recombination telomere de-SUMOylation and thus dissolution of ALT telomere clusters, leading to gross chromosome missegregation and mitotic cell death. These findings together establish KDM2A as a selective molecular vulnerability and a promising drug target for ALT-dependent cancers.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":398473,"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":0.9596,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":893093,"name":"Yizhe Wang","orcid":"0000-0002-6892-6729","position":1,"is_corresponding":false},{"id":457433,"name":"Inah Hwang","orcid":"0000-0002-4479-9374","position":2,"is_corresponding":false},{"id":893594,"name":"Ja-Young Jang","orcid":null,"position":3,"is_corresponding":false},{"id":1061545,"name":"Libo Xu","orcid":"0000-0002-8058-9868","position":4,"is_corresponding":false},{"id":362556,"name":"Zhong Deng","orcid":null,"position":5,"is_corresponding":false},{"id":441779,"name":"Eun Young Yu","orcid":"0000-0003-4252-3443","position":6,"is_corresponding":false},{"id":663442,"name":"Yiming Cai","orcid":"0000-0003-3533-1953","position":7,"is_corresponding":false},{"id":719745,"name":"Caizhi Wu","orcid":"0000-0002-2449-2818","position":8,"is_corresponding":false},{"id":1062170,"name":"Zhenbo Han","orcid":null,"position":9,"is_corresponding":false},{"id":1061546,"name":"Yuhan Huang","orcid":"0000-0002-0091-1627","position":10,"is_corresponding":false},{"id":384078,"name":"Xiangao Huang","orcid":null,"position":11,"is_corresponding":false},{"id":1174669,"name":"Ling Zhang","orcid":"0000-0002-0298-8855","position":12,"is_corresponding":false},{"id":114638,"name":"Jun Yao","orcid":null,"position":13,"is_corresponding":false},{"id":441783,"name":"Neal F. Lue","orcid":"0000-0001-9700-6895","position":14,"is_corresponding":false},{"id":299552,"name":"Paul M. Lieberman","orcid":"0000-0002-3935-9921","position":15,"is_corresponding":false},{"id":309159,"name":"Haoqiang Ying","orcid":"0000-0003-0616-2310","position":16,"is_corresponding":false},{"id":457434,"name":"Jihye Paik","orcid":"0000-0002-5481-2202","position":17,"is_corresponding":false},{"id":281249,"name":"Hongwu Zheng","orcid":"0000-0002-5823-4913","position":18,"is_corresponding":false},{"id":561481,"name":"Fei Li","orcid":"0000-0002-7818-6525","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:19:47.744358Z","pmid":"36798426","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":[]}