When the number of chromosomes goes off track 🧬

The improper segregation of chromosomes during cell division leads to abnormalities that disrupt the proper functioning of the cell. Cells with an abnormal number of chromosomes consequently activate mechanisms to prevent their propagation. In a study published in Nature Cell Biology, scientists reveal how these chromosomal abnormalities are detected. These findings shed light on a previously unknown role of nuclear mechanics in this process.

Aneuploidy and its consequences on the cell

Aneuploidy, a state where 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 out of two cancers, these cells can continue to divide, accumulate more mutations, and ultimately lead to the development of cancer. How abnormalities in chromosome number 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 mitoses in a controlled manner, scientists, in a paper published in the journal Nature Cell Biology, 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 interactions impact genome integrity and cellular function. Scientists discovered that the altered nuclear shape induced by mitotic errors affects chromatin organization, proper lamina assembly, and nuclear mechanics, overall reducing nuclear rigidity and increasing nuclear envelope tension.

The shape and mechanics of the nucleus are known to be influenced by the organization of DNA with its associated proteins (collectively called chromatin) inside the nucleus, as well as by the state of the filamentous protein network surrounding the nucleus, the nuclear lamina.

"We were surprised to find that structural abnormalities of the nucleus were sufficient to trigger the p53 checkpoint. This indicates that cells monitor the state of the chromatin-nuclear lamina interface. This mechanism acts as a checkpoint, preventing the proliferation of aneuploid cells," explains Yekaterina Miroshnikova, senior author of the study.

The scientists also identified the molecular mechanisms that detect these mechanical and shape abnormalities of the nucleus and demonstrated that chemical inhibitors targeting these pathways, particularly the mTOR and ATR signaling pathways, can prevent p53 activation.

"Importantly, we found that this surveillance mechanism is used in various other contexts. For example, it is activated in aging-related situations, such as in a disease called progeria, characterized by symptoms of premature aging in patients and by impaired nuclear lamina assembly at the cellular level. These findings highlight the crucial role of detecting nuclear mechanical abnormalities in various pathological contexts," explains Daniele Fachinetti, senior author of the study.


In conclusion, these findings shed light on how cells detect abnormal chromatin organization and chromosomal abnormalities, activating a protective checkpoint to prevent the 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 demonstrate that increased nuclear flexibility enhances the ability of aneuploid cells to deform and invade complex environments, a process that can promote metastasis, especially when the checkpoint is bypassed by p53 mutations, which are common in cancers.

Thus, nuclear mechanics emerges as a promising avenue for better detecting and targeting pathological cells in the context of cancer and aging-related diseases.


Reference:
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://doi.org/10.1038/s41556-024-01565-x