p53 preserves genome stability in dividing cells under hypo-osmotic stress

Cells respond to frequent osmotic stress to maintain structural integrity and function. Whereas acute volume regulation is well-known, the cellular response to prolonged osmotic stress and its long-term consequences remain poorly understood. In this study, we investigate how lasting hypo-osmotic stress influences cell growth and division and the associated cellular response. We observe that cells undergoing their first division under hypo-osmotic stress experience delayed mitotic entry, lengthened mitotic duration, elevated mitotic errors and aneuploidy formation. However, continued cell division is halted through a p53/p21-dependent G 1 arrest. p53 activation occurs post-mitotically and is associated with hyper-condensed chromatin and impaired nuclear expansion in daughter cells after mitotic exit. We show that the altered nuclear size dynamics lead to nuclear accumulation of p53 and activation of downstream gene expression. These findings uncover a mechanosensitive, p53-mediated mechanism that safeguards genome integrity by suppressing erroneous mitosis under hypo-osmotic stress.