{"doi":"10.17615/mned-p064","title":"Non-canonical Bromodomain within DNA-PKcs Promotes DNA Damage Response and Radioresistance through Recognizing an IR-Induced Acetyl-Lysine on H2AX","abstract":"Regulatory mechanisms underlying γH2AX induction and the associated cell fate decision during DNA damage response (DDR) remain obscure. Here, we discover a bromodomain (BRD)-like module in DNA-PKcs (DNA-PKcs-BRD) that specifically recognizes H2AX acetyl-lysine 5 (K5ac) for sequential induction of γH2AX and concurrent cell fate decision(s). First, top-down mass spectrometry of radiation-phenotypic, full-length H2AX revealed a radiation-inducible, K5ac-dependent induction of γH2AX. Combined approaches of sequence-structure modeling/docking, site-directed mutagenesis, and biochemical experiments illustrated that through docking on H2AX K5ac, this non-canonical BRD determines not only the H2AX-targeting activity of DNA-PKcs but also the over-activation of DNA-PKcs in radioresistant tumor cells, whereas a Kac antagonist, JQ1, was able to bind to DNA-PKcs-BRD, leading to re-sensitization of tumor cells to radiation. This study elucidates the mechanism underlying the H2AX-dependent regulation of DNA-PKcs in ionizing radiation-induced, differential DDR, and derives an unconventional, non-catalytic domain target in DNA-PKs for overcoming resistance during cancer radiotherapy.","journal":"UNC Libraries","year":2020,"id":137250,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9672,"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":538073,"name":"Feng Liu","orcid":"0000-0003-2669-5448","position":1,"is_corresponding":false},{"id":525192,"name":"Jian Jin","orcid":"0000-0001-9685-3355","position":2,"is_corresponding":false},{"id":149320,"name":"Nikolay V. Dokholyan","orcid":"0000-0002-8225-4025","position":3,"is_corresponding":false},{"id":11742,"name":"Xian Chen","orcid":"0000-0002-8358-1247","position":4,"is_corresponding":false},{"id":71449,"name":"Brian D. Strahl","orcid":"0000-0002-4947-6259","position":5,"is_corresponding":false},{"id":547006,"name":"Srinivas Ramachandran","orcid":"0000-0003-2929-1377","position":6,"is_corresponding":false},{"id":275708,"name":"Krzysztof Krajewski","orcid":"0000-0001-7159-617X","position":7,"is_corresponding":false},{"id":597258,"name":"Cheng Zhu","orcid":"0009-0006-2196-6914","position":8,"is_corresponding":false},{"id":307162,"name":"Li Wang","orcid":"0000-0001-7415-5599","position":9,"is_corresponding":false},{"id":57593,"name":"Ling Xie","orcid":"0000-0002-3577-8774","position":10,"is_corresponding":false},{"id":453045,"name":"Li Zhou","orcid":"0000-0001-7707-3468","position":11,"is_corresponding":false},{"id":260532,"name":"Zhen Yan","orcid":"0000-0002-4826-9813","position":12,"is_corresponding":false},{"id":597822,"name":"Yuan Yu Lee","orcid":null,"position":13,"is_corresponding":false},{"id":597257,"name":"David J. Chen","orcid":"0000-0003-0046-6903","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:16:56.001887Z","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":[]}