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When chromosome number gets out of hand: a novel mechanism to protect genome integrity

20/01/2025

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Quand le nombre de chromosomes déraille  un mécanisme inédit pour protéger l’intégrité du génome

Incorrect chromosome segregation during cell division leads to abnormalities that disrupt cell function. Cells with abnormal chromosome numbers consequently activate mechanisms to prevent their propagation. In a study published in Nature Cell Biology, Dr. Daniele Fachinetti's team (CNRS UMR3664 and UMR144) at Institut Curie reveals how these chromosomal abnormalities are detected. These results highlight a novel role for the mechanics of the nucleus in this process.

Aneuploidy and its consequences for the cell

Aneuploidy, a condition in which cells have an incorrect number of chromosomes, is observed in 90% of solid tumors. It results from errors in the segregation of chromosomes from the mother cell to the two daughter cells during mitosis, i.e. cell division, and leads to the activation of p53, a key protein that prevents abnormal cells from dividing. When p53 is mutated, which occurs on average in one in two cancers, these cells can continue to divide, accumulate more mutations and, ultimately, lead to the development of cancer. How chromosome number abnormalities are detected to activate this pathway remains an open question in cancer research.

The role of nuclear mechanics in detecting segregation errors

Using a genetic system to induce abnormal mitosis in a controlled manner, the Molecular Mechanisms of Chromosome Dynamics team (CNRS UMR3664 and UMR144) led by Dr. Daniele Fachinetti at Institut Curie, in a paper published in the journal Nature Cell Biology, have demonstrated that chromosome segregation errors alter the shape of the nucleus as well as its mechanical properties. The shape and mechanics of the nucleus are known to be influenced by internal factors, such as the organization of chromatin (the structure containing DNA) and the nuclear lamina (a network of proteins supporting the nucleus), as well as by external mechanical forces. These complex interactions impact genome integrity and cellular function. Scientists have discovered that the altered nuclear shape induced by mitotic errors affects chromatin organization, correct lamina assembly and nuclear mechanics, globally reducing nuclear rigidity and increasing nuclear envelope tension.

The shape and mechanics of the nucleus are known to be influenced by internal factors, such as the organization of chromatin (the structure containing DNA) and the nuclear lamina (a network of proteins supporting the nucleus), as well as by external mechanical forces. "We were surprised to find that structural abnormalities in the nucleus were sufficient to trigger the p53 checkpoint. This indicates that cells are monitoring the state of the chromatin-nuclear lamina interface. This mechanism acts as a checkpoint, preventing the proliferation of aneuploid cells", explains Dr. Yekaterina Miroshnikova, senior author of the study.

The scientists also identified the molecular mechanisms that detect these mechanical and shape abnormalities in the nucleus, and demonstrated that chemical inhibitors targeting these pathways, including the mTOR and ATR signaling pathways, can prevent p53 activation. "Importantly, we discovered that this surveillance mechanism is used in a variety of other contexts. For example, it is activated in age-related situations, such as in a disease called progeria, characterized by premature ageing symptoms in patients and altered nuclear lamina assembly at the cellular level. These results underline the crucial role of detecting mechanical abnormalities of the nucleus in various pathological contexts", explains Dr. Daniele Fachinetti, senior author of the study.

In conclusion, these results shed light on how cells detect abnormal chromatin organization and chromosomal abnormalities, activate a protective checkpoint to prevent proliferation of dysfunctional cells. Although the detection of nuclear mechanical alterations limits the proliferation of abnormal cells, these changes can also have detrimental effects. For example, scientists are demonstrating that increased flexibility of the nucleus enhances the ability of aneuploid cells to deform and invade complex environments, a process that can promote metastasis, particularly when the checkpoint is bypassed by p53 mutations, common in cancers.

Nuclear mechanics is thus emerging as a promising avenue for better detection and targeting of pathological cells in cancer and age-related diseases.
 

Figure

A mechanoreceptive nuclear checkpoint causes cell cycle arrest after chromosome mis-segregation. Errors in chromosome segregation during mitosis, induced for example by centromere dysfunction (red dots represent inactive centromeres), lead to deformation and softening of the nucleus, reduced levels of heterochromatin at the nuclear periphery and defects in lamin assembly. These alterations increase tension on the nuclear envelope of daughter cells, leading to activation of the mTORC2 and ATR mechanoreceptors, triggering cell cycle arrest in a p53- and p21-dependent manner.

Références

Hervé, S., Scelfo, A., Bersano Marchisio, G. et al. Chromosome mis-segregation triggers cell cycle arrest through a mechanosensitive nuclear envelope checkpoint. Nat Cell Biol 27, 73–86 (2025). https://www.nature.com/articles/s41556-024-01565-x

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