Chromosome mis-segregation triggers cell cycle arrest through a mechanosensitive nuclear envelope checkpoint
Errors during cell division lead to aneuploidy, which is associated with genomic instability and cell transformation. In response to aneuploidy, cells activate the tumour suppressor p53 to elicit a surveillance mechanism that halts proliferation and promotes senescence. The molecular sensors that trigger this checkpoint are unclear. Here, using a tunable system of chromosome mis-segregation, we show that mitotic errors trigger nuclear deformation, nuclear softening, and lamin and heterochromatin alterations, leading to rapid p53/p21 activation upon mitotic exit in response to changes in nuclear mechanics. We identify mTORC2 and ATR as nuclear deformation sensors upstream of p53/p21 activation. While triggering mitotic arrest, the chromosome mis-segregation-induced alterations of nuclear envelope mechanics provide a fitness advantage for aneuploid cells by promoting nuclear deformation resilience and enhancing pro-invasive capabilities. Collectively, this work identifies a nuclear mechanical checkpoint triggered by altered chromatin organization that probably plays a critical role in cellular transformation and cancer progression.
Authors
- Daniele Fachinetti (ORCID: https://orcid.org/0000-0002-8795-6771)
- Anne‐Sophie Macé (ORCID: https://orcid.org/0000-0003-3072-3819)
- Alice Williart (ORCID: https://orcid.org/0000-0003-2581-0379)
- Gianluca Pegoraro (ORCID: https://orcid.org/0000-0003-2843-9464)
- Marie Dumont (ORCID: https://orcid.org/0000-0002-0636-0731)
- Annapaola Angrisani (ORCID: https://orcid.org/0000-0002-3407-7669)
- Solène Hervé (ORCID: https://orcid.org/0000-0002-5015-8493)
- Andrea Scelfo (ORCID: https://orcid.org/0000-0001-8767-0688)
- Kotryna Vaidžiulytė (ORCID: https://orcid.org/0000-0002-2114-3612)
- G. Nader (ORCID: https://orcid.org/0000-0002-1905-1903)
- Matteo Gentili (ORCID: https://orcid.org/0000-0002-6970-8133)
- Matthieu Piel (ORCID: https://orcid.org/0000-0002-2848-177X)
- Nicolas Manel (ORCID: https://orcid.org/0000-0002-1481-4430)
- Adib Keikhosravi (ORCID: https://orcid.org/0000-0002-7901-1276)
- Mathieu Deygas (ORCID: https://orcid.org/0000-0003-3417-8133)
- Yekaterina A. Miroshnikova (ORCID: https://orcid.org/0000-0001-9771-4963)
- Marine Grison
- Gabriele Bersano Marchisio
Institutions
- Centre National de la Recherche Scientifique (FR)
- National Institutes of Health (US)
- Children's Hospital of Philadelphia (US)
- Inserm (FR)
- Université Paris Sciences et Lettres (FR)
- Sorbonne Université (FR)
- National Institute of Diabetes and Digestive and Kidney Diseases (US)
- Institut Pierre-Gilles de Gennes pour la Microfluidique (FR)
- National Cancer Institute (US)
- Dynamique du noyau (FR)
- High Throughput Biology (United States) (US)
- Biologie cellulaire et Cancer (FR)
- University of Pennsylvania (US)
- Institut Curie (FR)
Publication Details
- Journal
- Nature Cell Biology
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1038/s41556-024-01565-x
- Citations
- 31
- Primary Topic
- Nuclear Structure and Function
- Type
- article
- Field-Weighted Citation Impact
- 24.18
Funders
- Infrastructures en Biologie Santé et Agronomie
- Imperial College London
- European Commission
- Agence Nationale de la Recherche
- Centre National de la Recherche Scientifique
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases