Background <p>Dynamic physical changes in the extracellular environment of living tissues present a mechanical challenge for resident cells that can lead to damage to the nucleus, genome, and DNA. Recent studies have started to uncover nuclear mechanoprotection mechanisms that prevent excessive mechanical deformations of the nucleus. Here, we hypothesized that dynamic topographical changes in the cellular environment can be mechanically transmitted to the nucleus and trigger nuclear mechanoprotection events. We tested this using a photoresponsive hydrogel whose surface topography can be reversibly changed on demand upon light illumination, allowing us to subject cells to recurring microscale topographical changes.</p> Results <p>With each recurring topographical change, fibroblasts were found to increasingly compact and relocate their nuclei away from the dynamic regions of the hydrogel. These cell-scale reorganization events were accompanied by an increase of global histone acetylation and decreased methylation in cells on the dynamic topographies, resulting in a minimization of DNA strand breakage. We further found that these nuclear mechanoprotection events were mediated by both vimentin intermediate filaments and the actin cytoskeleton.</p> Conclusions <p>Together, these data reveal that fibroblasts actively protect their nuclei in the presence of dynamic topographical changes through cytoskeleton-mediated mechanisms. Broadly, these results stress the importance of gaining a deeper fundamental understanding of the cellular mechanoresponse under dynamically changing conditions.</p>