{"doi":"10.1101/2021.02.26.433034","title":"Cell-to-cell heterogeneities during extrinsic apoptosis arise from cell cycle progression and transmitotic apoptosis resistance","abstract":"Abstract Extrinsic apoptosis relies on TNF-family receptor activation by immune cells or receptor-activating biologics. Here, we monitored cell cycle progression at minutes resolution to relate apoptosis kinetics and cell-to-cell heterogeneities in death decisions to cell cycle phases. Interestingly, we found that cells in S phase delay TRAIL receptor-induced death in favour for mitosis, thereby passing on an apoptosis-primed state to their offspring. This translates into two distinct fates, apoptosis execution post mitosis or cell survival from inefficient apoptosis. Transmitotic resistance is linked to Mcl-1 upregulation from mid S phase onwards, which allows cells to pass through mitosis with activated caspase-8, and with cells escaping apoptosis after mitosis sustaining sublethal DNA damage. Antagonizing Mcl-1 by BH3-mimetics suppresses cell cycle-dependent delays in apoptosis, prevents apoptosis-resistant progression through mitosis and averts unwanted survival from apoptosis induction. Cell cycle progression therefore modulates signal transduction during extrinsic apoptosis, with Mcl-1 governing decision making between death, proliferation and survival from inefficient apoptosis induction. Cell cycle progression thus is a crucial process from which cell-to-cell heterogeneities in fates and treatment outcomes emerge in isogenic cell populations during extrinsic apoptosis signalling.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":223463,"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":0.958,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":824923,"name":"Aline Lindner","orcid":"0000-0002-8654-9592","position":1,"is_corresponding":false},{"id":824924,"name":"Dirke Imig","orcid":"0000-0002-1884-942X","position":2,"is_corresponding":false},{"id":824925,"name":"Karsten Kuritz","orcid":"0000-0002-5452-8957","position":3,"is_corresponding":false},{"id":824926,"name":"Jacques S. Fritze","orcid":"0000-0001-8484-8567","position":4,"is_corresponding":false},{"id":824927,"name":"Isabel Heinrich","orcid":"0000-0003-4310-6748","position":5,"is_corresponding":false},{"id":824928,"name":"Jannis Stadager","orcid":"0000-0001-6069-8322","position":6,"is_corresponding":false},{"id":353394,"name":"Stephan A. Eisler","orcid":"0000-0002-6503-6966","position":7,"is_corresponding":false},{"id":825365,"name":"Daniela Stöhr","orcid":null,"position":8,"is_corresponding":false},{"id":39661,"name":"Frank Allgöwer","orcid":"0000-0002-3702-3658","position":9,"is_corresponding":false},{"id":825366,"name":"Peter Scheurich","orcid":null,"position":10,"is_corresponding":false},{"id":824929,"name":"Markus Rehm","orcid":"0000-0001-6149-9261","position":11,"is_corresponding":false},{"id":824922,"name":"Nadine Pollak","orcid":"0000-0002-0718-2156","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-18T23:54:11.061295Z","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":[]}