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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月8日

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  • Solène Hervé,
  • Andrea Scelfo,
  • Gabriele Bersano Marchisio,
  • Marine Grison,
  • Kotryna Vaidžiulytė,
  • Marie Dumont,
  • Annapaola Angrisani,
  • Adib Keikhosravi,
  • Gianluca Pegoraro,
  • Mathieu Deygas,
  • Guilherme P. F. Nader,
  • Anne-Sophie Macé,
  • Matteo Gentili,
  • Alice Williart,
  • Nicolas Manel,
  • Matthieu Piel,
  • Yekaterina A. Miroshnikova,
  • Daniele Fachinetti

摘要

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.