{"doi":"10.1101/2023.01.17.524444","title":"p53 controls choice between apoptotic and non-apoptotic death following DNA damage","abstract":"DNA damage can activate apoptotic and non-apoptotic forms of cell death; however, it remains unclear what features dictate which type of cell death is activated. We report that p53 controls the choice between apoptotic and non-apoptotic death following exposure to DNA damage. In contrast to the conventional model, which suggests that p53-deficient cells should be resistant to DNA damage-induced cell death, we find that p53-deficient cells die at high rates following DNA damage, but exclusively using non-apoptotic mechanisms. Our experimental data and computational modeling reveal that non-apoptotic death in p53-deficient cells has not been observed due to use of assays that are either insensitive to cell death, or that specifically score apoptotic cells. Using functional genetic screening - with an analysis that enables computational inference of the drug-induced death rate - we find in p53-deficient cells that DNA damage activates a mitochondrial respiration-dependent form of cell death, called MPT-driven necrosis. Cells deficient for p53 have high basal respiration, which primes MPT-driven necrosis. Finally, using metabolite profiling, we identified mitochondrial activity-dependent metabolic vulnerabilities that can be targeted to potentiate the lethality of DNA damage specifically in p53-deficient cells. Our findings reveal how the dual functions of p53 in regulating mitochondrial activity and the DNA damage response combine to facilitate the choice between apoptotic and non-apoptotic death.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":392873,"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":0.9561,"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":630121,"name":"Marie S. Isidor","orcid":"0000-0003-3396-5389","position":1,"is_corresponding":false},{"id":632370,"name":"Nicholas W. Harper","orcid":"0000-0002-4037-7473","position":2,"is_corresponding":false},{"id":566802,"name":"Rachel E. Fontana","orcid":null,"position":3,"is_corresponding":false},{"id":1167198,"name":"Peter Cruz- Gordillo","orcid":null,"position":4,"is_corresponding":false},{"id":1166834,"name":"Sydney A Porto","orcid":"0009-0009-7329-404X","position":5,"is_corresponding":false},{"id":650937,"name":"Cameron Fraser","orcid":"0000-0002-8180-5913","position":6,"is_corresponding":false},{"id":650944,"name":"Kristopher A. Sarosiek","orcid":"0000-0002-4618-5085","position":7,"is_corresponding":false},{"id":257492,"name":"David A. Guertin","orcid":"0000-0003-3695-6007","position":8,"is_corresponding":false},{"id":555944,"name":"Jessica B. Spinelli","orcid":"0000-0003-3657-4578","position":9,"is_corresponding":false},{"id":511584,"name":"Michael J. Lee","orcid":"0000-0003-3378-6196","position":10,"is_corresponding":false},{"id":566352,"name":"Megan E. Honeywell","orcid":"0000-0002-4894-8672","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-19T01:19:01.355412Z","pmid":"36712034","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":[]}