法国巴黎PSL大学Daniele Fachinetti等合作揭示，染色体错分通过机械敏感的核膜检查点触发细胞周期阻滞。2025年1月8日出版的《自然—细胞生物学》杂志发表了这项成果。

据介绍，细胞分裂中的错误会导致染色体数目异常（非整倍体），与基因组不稳定性和细胞转化相关。面对非整倍体，细胞激活肿瘤抑制因子p53，启动一种监控机制，停止细胞增殖并促进衰老。然而，触发这一检查点的分子传感器尚不明确。

在本研究中，通过使用可调节的染色体错分系统，发现有丝分裂错误会引发核形变、核软化以及核纤层和异染色质的改变，导致在有丝分裂退出后，响应核力学变化迅速激活p53/p21。研究人员鉴定了mTORC2和ATR作为p53/p21激活的上游核形变传感器。

尽管染色体错分引发的改变会触发有丝分裂停滞，但这些核膜力学的改变，通过促进核形变的适应性和增强侵袭性能力，为非整倍体细胞提供了生存优势。

总体而言，本研究揭示了一种由染色质组织改变引发的核机械检查点，可能在细胞转化和癌症进展中发挥关键作用。

附：英文原文

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

Author: Herv, Solne, Scelfo, Andrea, Bersano Marchisio, Gabriele, Grison, Marine, Vaidiulyt, Kotryna, Dumont, Marie, Angrisani, Annapaola, Keikhosravi, Adib, Pegoraro, Gianluca, Deygas, Mathieu, P. F. Nader, Guilherme, Mac, Anne-Sophie, Gentili, Matteo, Williart, Alice, Manel, Nicolas, Piel, Matthieu, Miroshnikova, Yekaterina A., Fachinetti, Daniele

Issue&Volume: 2025-01-08

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.

DOI: 10.1038/s41556-024-01565-x

Source: https://www.nature.com/articles/s41556-024-01565-x