RAD51 up- or down regulation is highly toxic to human transformed cells through the induction of replication stress, G2/M arrest and apoptosisDownload PDF Download PDF ArticleOpen accessPublished: 13 October 2026Melissa Thomas ORCID: orcid.org/0009-0006-4754-86651,2,Alessandra Poma1,Nine le Dilly1,Elodie Dardillac1,Stéphane Koundrioukoff3,Quentin Delacour4,5,Jean-Philippe Morretton4,5,Ayeong So1,Michelle Debatisse ORCID: orcid.org/0000-0002-7113-39653,Olivier Gavet4,5,Jean-Yves Masson ORCID: orcid.org/0000-0002-4403-71692,Bernard Lopez ORCID: orcid.org/0000-0001-5088-01551 &…Josée Guirouilh-Barbat ORCID: orcid.org/0000-0002-8845-73331,6 Cell Death & Disease (2026) Cite this articleSave articleView saved research We’re sharing this article early to provide faster access to peer-reviewed, accepted research. It is citable and carries a permanent DOI. This version is subject to further edits and will be replaced automatically by the final Version of Record. All legal disclaimers apply.AbstractHomologous recombination (HR) plays a central role in DNA repair and replication, and consequently in the maintenance of genome stability. Although most HR genes are essential in non-malignant proliferating cells, many of them are mutated in cancers. This implies that either actively proliferating cancer cells have adapted to cope with HR defects or HR proteins became dispensable in this context. Here, we observed that prolonged inhibition of HR results in severe toxicity in a variety of transformed human cells, dismissing the latter hypothesis. We then show that HR deficient cells experience a massive replication stress, and that their cell cycle is blocked in late G2 before entry into mitosis. This cell cycle arrest is not mediated by the activation of the ATR/CHK1 axis but by downregulation of Cyclin B1 and then leads to apoptosis. Intriguingly, RAD51, which plays a pivotal role in HR, is overexpressed rather than inactivated in cancers. We show that overexpression of wild-type RAD51 also impedes replication and triggers apoptosis in transformed cells, which points to a unifying mechanism of cell death upon HR dysregulation. Our results underscore the importance of tight control of HR for maintaining cell viability and also imply that HR dysregulated tumor cells have adapted to escape cell cycle arrest and induction of apoptosis.Cells dysregulated for HR, either overexpressing WT-RAD51 or deficient for HR, undergo a massive replication stress but do not activate the canonical ATR/CHK1 axis. Therefore, cells do not accumulate in the S phase but progress until the late G2 phase, where downregulation of CyclinB1 prevents their entry into mitosis. The sustained cell cycle block in late G2 leads to cell death by apoptosis. Cells that escape this checkpoint have likely adapted to cope with HR dysregulation or to relieve replication stress, cell cycle checkpoint or induction of apoptosis.AcknowledgementsWe would like to thank Viviane Lebrec for technical help.FundingThis work was supported by grants from the Association pour la Recherche contre le Cancer (ARC PJA ARCPJA2021060003792 and ARCPJA2022060005157), Institut National du Cancer (PLBIO21-072, PLBIO24-200-2024-161 and PLBIO24-196-2024-158), La Ligue Contre Le Cancer (AO ARN therapeutiques), and the Canadian Institutes of Health Research (PJT-517664 to JYM). JYM is a Canada Research Chair in DNA repair and Cancer Therapeutics. JPM, QD and OG were funded by Agence Nationale de la Recherche (ANR- 17-CE13-0011 and ANR-20-CE12-0027).Author informationAuthors and AffiliationsUniversité de Paris Cité, INSERM U1016, UMR 8104 CNRS, Institut Cochin, Paris, FranceMelissa Thomas, Alessandra Poma, Nine le Dilly, Elodie Dardillac, Ayeong So, Bernard Lopez & Josée Guirouilh-BarbatCHU de Quebec Research Center, Oncology Division, Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Quebec City PQ, QC, CanadaMelissa Thomas & Jean-Yves MassonGustave Roussy Institute, Sorbonne Université, UPMC, Villejuif, FranceStéphane Koundrioukoff & Michelle DebatisseSorbonne Université, Faculté des Sciences et Ingénierie, Paris, FranceQuentin Delacour, Jean-Philippe Morretton & Olivier GavetUMR9019 CNRS, Université Paris-Saclay, Gustave Roussy, Villejuif, FranceQuentin Delacour, Jean-Philippe Morretton & Olivier GavetInstitut Curie, PSL Research University, Sorbonne Université, CNRS, UMR144 and UMR3664, Paris, FranceJosée Guirouilh-BarbatAuthorsMelissa ThomasView author publicationsSearch author on:PubMed Google ScholarAlessandra PomaView author publicationsSearch author on:PubMed Google ScholarNine le DillyView author publicationsSearch author on:PubMed Google ScholarElodie DardillacView author publicationsSearch author on:PubMed Google ScholarStéphane KoundrioukoffView author publicationsSearch author on:PubMed Google ScholarQuentin DelacourView author publicationsSearch author on:PubMed Google ScholarJean-Philippe MorrettonView author publicationsSearch author on:PubMed Google ScholarAyeong SoView author publicationsSearch author on:PubMed Google ScholarMichelle DebatisseView author publicationsSearch author on:PubMed Google ScholarOlivier GavetView author publicationsSearch author on:PubMed Google ScholarJean-Yves MassonView author publicationsSearch author on:PubMed Google ScholarBernard LopezView author publicationsSearch author on:PubMed Google ScholarJosée Guirouilh-BarbatView author publicationsSearch author on:PubMed Google ScholarCorresponding authorsCorrespondence to Bernard Lopez or Josée Guirouilh-Barbat.Ethics declarationsCompeting interestsThe author(s) declare no competing interests.Ethics approval and consent to participateAll methods were performed in accordance with the relevant guidelines and regulations. Ethics approval was not needed because no patients were involved and no animals were used.Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Edited by Dr Angelo PeschiaroliSupplementary informationRights and permissionsOpen Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Reprints and permissionsAbout this article