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
  • 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. [email protected].
  • 9. CNRS UMR144 - UMR3664, Institut Curie, Sorbonne Université, PSL Research University, Paris, France. [email protected].
  • # 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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