{"doi":"10.1101/2020.04.01.021253","title":"Hyperactive end joining repair mediates resistance to DNA damaging therapy in p53-deficient cells","abstract":"Abstract TP53 mutations in cancer are associated with poor patient outcomes and resistance to DNA damaging therapies 1–3 . However, the mechanisms underlying treatment resistance in p53-deficient cells remain poorly characterized. Here, we show that p53-deficient cells exhibit hyperactive repair of therapy-induced DNA double strand breaks (DSBs), which is suppressed by inhibition of DNA-dependent protein kinase (DNA-PK). Single-cell analyses of DSB repair kinetics and cell cycle state transitions reveal an essential role for DNA-PK in suppressing S phase DNA damage and mitotic catastrophe in p53-deficient cells. Yet, a subset of p53-deficient cells exhibit intrinsic resistance to therapeutic DSBs due to a repair pathway that is not sensitive to DNA-PK inhibition. We show that p53 deficiency induces overexpression of DNA Polymerase Theta (Pol θ), which mediates an alternative end-joining repair pathway that becomes hyperactivated by DNA-PK inhibition 4 . Combined inhibition of DNA-PK and Pol θ restores therapeutic DNA damage sensitivity in p53-deficient cells. Thus, our study identifies two targetable DSB end joining pathways that can be suppressed as a strategy to overcome resistance to DNA-damaging therapies in p53-deficient cancers.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":122671,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9524,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":281293,"name":"Hui Chao","orcid":"0000-0003-4153-5303","position":1,"is_corresponding":false},{"id":476098,"name":"Victoria Roberts","orcid":null,"position":2,"is_corresponding":false},{"id":476099,"name":"Aurora R Sullivan","orcid":null,"position":3,"is_corresponding":false},{"id":475125,"name":"Sonam Shah","orcid":"0009-0005-3608-5207","position":4,"is_corresponding":false},{"id":436438,"name":"Dennis A. Simpson","orcid":"0000-0001-5332-8243","position":5,"is_corresponding":false},{"id":476097,"name":"Wanjuan Feng","orcid":null,"position":6,"is_corresponding":false},{"id":475126,"name":"Anne‐Sophie Wozny","orcid":"0000-0003-0247-2653","position":7,"is_corresponding":false},{"id":475127,"name":"Sunil Kumar","orcid":"0000-0002-6282-0640","position":8,"is_corresponding":false},{"id":466075,"name":"Jeremy E. Purvis","orcid":"0000-0002-6963-0524","position":9,"is_corresponding":false},{"id":457309,"name":"Gaorav P. Gupta","orcid":"0000-0001-9177-552X","position":10,"is_corresponding":false},{"id":457306,"name":"Rashmi J. Kumar","orcid":"0000-0002-8742-2753","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-18T23:14:55.385653Z","pmid":null,"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":[]}