DNA damage‐induced replication stress results in PA200‐proteasome‐mediated degradation of acetylated histones

Histone acetylation influences protein interactions and chromatin accessibility and plays an important role in the regulation of transcription, replication, and DNA repair. Conversely, DNA damage affects these crucial cellular processes and induces changes in histone acetylation. However, a comprehensive overview of the effects of DNA damage on the histone acetylation landscape is currently lacking. To quantify changes in histone acetylation, we developed an unbiased quantitative mass spectrometry analysis on affinity‐purified acetylated histone peptides, generated by differential parallel proteolysis. We identify a large number of histone acetylation sites and observe an overall reduction of acetylated histone residues in response to DNA damage, indicative of a histone‐wide loss of acetyl modifications. This decrease is mainly caused by DNA damage‐induced replication stress coupled to specific proteasome‐dependent loss of acetylated histones. Strikingly, this degradation of acetylated histones is independent of ubiquitylation but requires the PA200‐proteasome activator, a complex that specifically targets acetylated histones for degradation. The uncovered replication stress‐induced degradation of acetylated histones represents an important chromatin‐modifying response to cope with replication stress. Synopsis In response to replication stress, acetylated histones are degraded by the PA200‐proteasome complex, which is an important chromatin‐modifying response for cells to cope with replication stress. Histone acetylation levels are decreased upon DNA damage‐induced replication stress. The PA200‐proteasome degrades acetylated histones upon replication stress. PA200 is necessary for cellular survival following replication stress. Graphical Abstract In response to replication stress, acetylated histones are degraded by the PA200‐proteasome complex, which is an important chromatin‐modifying response for cells to cope with replication stress.