2. Academic Validation
  3. Chromosome mis-segregation triggers cell cycle arrest through a mechanosensitive nuclear envelope checkpoint

Chromosome mis-segregation triggers cell cycle arrest through a mechanosensitive nuclear envelope checkpoint

  • Nat Cell Biol. 2025 Jan;27(1):73-86. doi: 10.1038/s41556-024-01565-x.
Solène Hervé # 1 2,  Andrea Scelfo # 1,  Gabriele Bersano Marchisio 1,  Marine Grison 1,  Kotryna Vaidžiulytė 3,  Marie Dumont 1,  Annapaola Angrisani 1,  Adib Keikhosravi 4,  Gianluca Pegoraro 4,  Mathieu Deygas 3,  Guilherme P F Nader 3 5,  Anne-Sophie Macé 1 6,  Matteo Gentili 7,  Alice Williart 3,  Nicolas Manel 7,  Matthieu Piel 3,  Yekaterina A Miroshnikova 8,  Daniele Fachinetti 9
Affiliations

Affiliations

  • 1 CNRS UMR144 - UMR3664, Institut Curie, Sorbonne Université, PSL Research University, Paris, France.
  • 2 Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
  • 3 CNRS UMR144, Institut Curie, Institut Pierre Gilles de Gennes, PSL Research University, Paris, France.
  • 4 High-Throughput Imaging Facility, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 5 Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  • 6 CNRS UMR144, Cell and Tissue Imaging Facility (PICT-IBiSA), Institut Curie, PSL Research University, Paris, France.
  • 7 INSERM U932, Institut Curie, PSL Research University, Paris, France.
  • 8 Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. yekaterina.miroshnikova@nih.gov.
  • 9 CNRS UMR144 - UMR3664, Institut Curie, Sorbonne Université, PSL Research University, Paris, France. daniele.fachinetti@curie.fr.
  • # Contributed equally.
PMID: 39779939 DOI: 10.1038/s41556-024-01565-x
Abstract

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.

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