Proteotoxic stress reprograms the chromatin landscape of SUMO modification

Abstract

The small ubiquitin-like modifier 2 (SUMO-2) is required for survival when cells are exposed to treatments that induce proteotoxic stress by causing the accumulation of misfolded proteins. Exposure of cells to heat shock or other forms of proteotoxic stress induces the conjugation of SUMO-2 to proteins in the nucleus. We investigated the chromatin landscape of SUMO-2 modifications in response to heat stress. Through chromatin immunoprecipitation assays coupled to high-throughput DNA sequencing and mRNA sequencing, we showed that in response to heat shock, SUMO-2 accumulated at nucleosome-depleted, active DNA regulatory elements, which represented binding sites for large protein complexes and were predominantly associated with active genes. However, SUMO did not act as a direct transcriptional repressor or activator of these genes during heat shock. Instead, integration of our results with published proteomics data on heat shock-induced SUMO-2 substrates supports a model in which the conjugation of SUMO-2 to proteins acts as an acute stress response that is required for the stability of protein complexes involved in gene expression and posttranscriptional modification of mRNA. We showed that the conjugation of SUMO-2 to chromatin-associated proteins is an integral component of the proteotoxic stress response, and propose that SUMO-2 fulfills its essential role in cell survival by contributing to the maintenance of protein complex homeostasis.