Satellite DNA condensation into chromocenters through charge-driven phase separation of DNA-binding proteins creates physical connections between chromosomes that dissipate mechanical forces across larger nuclear surface areas, establishing chromocenter coalescence as a tunable mechanism that safeguards nuclear mechanostability and genome integrity in mechanically challenged cells.

As the largest organelle, the nucleus endures significant mechanical stresses over the cellular lifespan, and mechanostability, i.e. the ability to resist deformation, is critical for genome integrity and function. Here, we reveal that nuclear mechanostability is an emergent property arising from the clustering of satellite DNA repeats into nuclear condensates known as chromocenters. Targeted chromocenter disruption in Drosophila testes subjected to natural and artificial mechanical stress compromises nuclear mechanostability, leading to deformed nuclei, DNA damage, and chromosome breaks. Conversely, enhancing chromocenter coalescence through genetic means improves mechanostability. Molecular dynamics simulations suggest that chromocenters enable physically linked chromosomes to respond collectively, rather than individually, to mechanical challenge, and dissipate external forces over a larger nuclear surface. We propose that the satellite DNA-dependent mechanostability framework described here likely extends to other cells and tissues facing mechanical stress, and offers an explanation for the evolutionary success of these non-coding repeats across eukaryotes.