{"doi":"10.1093/narcan/zcaa038","title":"Dual inhibition of DNA-PK and DNA polymerase theta overcomes radiation resistance induced by p53 deficiency","abstract":"deficiency in cancer is associated with poor patient outcomes and resistance to DNA damaging therapies. However, the mechanisms underlying treatment resistance in p53-deficient cells remain poorly characterized. Using live cell imaging of DNA double-strand breaks (DSBs) and cell cycle state transitions, we show that p53-deficient cells exhibit accelerated repair of radiomimetic-induced DSBs arising in S phase. Low-dose DNA-dependent protein kinase (DNA-PK) inhibition increases the S-phase DSB burden in p53-deficient cells, resulting in elevated rates of mitotic catastrophe. However, a subset of p53-deficient cells exhibits intrinsic resistance to radiomimetic-induced DSBs despite DNA-PK inhibition. We show that p53-deficient cells under DNA-PK inhibition utilize DNA polymerase theta (Pol θ)-mediated end joining repair to promote their viability in response to therapy-induced DSBs. Pol θ inhibition selectively increases S-phase DSB burden after radiomimetic therapy and promotes prolonged G2 arrest. Dual inhibition of DNA-PK and Pol θ restores radiation sensitivity in p53-deficient cells as well as in p53-mutant breast cancer cell lines. Thus, combination targeting of DNA-PK- and Pol θ-dependent end joining repair represents a promising strategy for overcoming resistance to DNA damaging therapies in p53-deficient cancers.","journal":"NAR Cancer","year":2020,"id":95668,"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":36,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9515,"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":436438,"name":"Dennis A. Simpson","orcid":"0000-0001-5332-8243","position":2,"is_corresponding":false},{"id":476097,"name":"Wanjuan Feng","orcid":null,"position":3,"is_corresponding":false},{"id":475124,"name":"Min-Guk Cho","orcid":"0000-0001-7122-267X","position":4,"is_corresponding":false},{"id":476098,"name":"Victoria Roberts","orcid":null,"position":5,"is_corresponding":false},{"id":476099,"name":"Aurora R Sullivan","orcid":null,"position":6,"is_corresponding":false},{"id":475125,"name":"Sonam Shah","orcid":"0009-0005-3608-5207","position":7,"is_corresponding":false},{"id":475126,"name":"Anne‐Sophie Wozny","orcid":"0000-0003-0247-2653","position":8,"is_corresponding":false},{"id":458181,"name":"Katerina D. Fagan‐Solis","orcid":null,"position":9,"is_corresponding":false},{"id":475127,"name":"Sunil Kumar","orcid":"0000-0002-6282-0640","position":10,"is_corresponding":false},{"id":475128,"name":"Adam J. Luthman","orcid":"0000-0001-6695-880X","position":11,"is_corresponding":false},{"id":448788,"name":"Dale A. Ramsden","orcid":"0000-0003-1575-4748","position":12,"is_corresponding":false},{"id":466075,"name":"Jeremy E. Purvis","orcid":"0000-0002-6963-0524","position":13,"is_corresponding":false},{"id":457309,"name":"Gaorav P. Gupta","orcid":"0000-0001-9177-552X","position":14,"is_corresponding":false},{"id":457306,"name":"Rashmi J. Kumar","orcid":"0000-0002-8742-2753","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":null,"created_at":"2026-07-18T22:33:57.534608Z","pmid":"33385162","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":[]}