Proteomic profiling of UV damage repair patches uncovers histone chaperones with central functions in chromatin repair

DNA damage compromises not only genome stability but also chromatin integrity, which plays a central role in controlling cell identity. Chromatin repair entails the deposition of new histones at sites of DNA damage. How this is coordinated with parental histone dynamics for the maintenance of chromatin states is unknown. To bridge this knowledge gap, here we devise a novel proteomic strategy to characterize dynamic changes in the chromatin landscape during the repair of UV-induced DNA lesions in human cells, in a quantitative, unbiased and time-resolved manner. Thus, we identify the histone chaperones DNAJC9 and MCM2 as central players in chromatin repair. DNAJC9 provides new H3-H4 histones to CAF-1 and HIRA chaperones for deposition into chromatin and stimulates old H3-H4 histone recovery. MCM2 cooperates with DNAJC9 to coordinate old and new histone dynamics during UV damage repair. Together, our proteomic dataset provides a molecular framework for further dissecting epigenome maintenance mechanisms. Chromatin states need to be maintained during DNA damage repair. Here, the authors expand the histone chaperone network involved in repair-coupled chromatin restoration and highlight a mechanistic coordination between old and new histone dynamics.