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

Area of Science:

• Cell Biology
• Cancer Biology
• Genomics

Background:

• Aneuploidy, arising from cell division errors, is linked to genomic instability and cancer.
• The tumor suppressor p53 pathway is activated by aneuploidy to halt cell proliferation.
• The precise molecular sensors initiating this p53-mediated checkpoint remain largely unknown.

Purpose of the Study:

• To elucidate the molecular mechanisms sensing aneuploidy and triggering the p53/p21 pathway.
• To investigate the role of nuclear mechanics in the cellular response to chromosome mis-segregation.
• To identify upstream sensors involved in the p53/p21 activation cascade.

Main Methods:

• Utilized a tunable system to induce chromosome mis-segregation.
• Monitored nuclear deformation, softening, and alterations in lamin and heterochromatin.
• Assessed p53/p21 activation upon mitotic exit and identified key signaling molecules (mTORC2, ATR).

Main Results:

• Mitotic errors induce significant nuclear deformation, softening, and changes in chromatin organization.
• These mechanical alterations trigger rapid p53/p21 activation after mitosis.
• mTORC2 and ATR were identified as critical sensors of nuclear deformation upstream of p53/p21.
• Altered nuclear mechanics confer a fitness advantage to aneuploid cells, enhancing resilience and invasiveness.

Conclusions:

• A novel nuclear mechanical checkpoint activated by chromatin alterations in response to aneuploidy has been identified.
• This checkpoint, involving mTORC2 and ATR, plays a crucial role in p53/p21 activation.
• The findings suggest a significant role for nuclear mechanics in cellular transformation and cancer progression.