Summary Stress adaptation is exploited by cancer cells to survive and proliferate under adverse conditions. Survival pathways induced by stress are thus highly promising therapeutic targets. One key pathway involves formation of cytoplasmic stress granules, which regulate the location, stability, and translation of specific mRNAs. Here, we describe a transcriptional stress response that is triggered by similar stressors and characterized by accumulation of RepoMan (cell division cycle associated 2) at nuclear stress foci (nucSF). Formation of these structures is reversible, and they are distinct from known nuclear organelles and stress bodies. Immunofluorescence analysis revealed accumulation of heterochromatic markers, and increased association of RepoMan with the adenylate cyclase 2 (ADCY2) gene locus in stressed cells accompanied reduced levels of ADCY2 mRNA and protein. Quantitative comparison of the RepoMan interactome in stressed vs. unstressed cells identified condensin II as a nucSF factor, suggesting their functional association in the establishment and/or maintenance of these facultative heterochromatic domains.