The proper function of DNA damage response pathways (DDR) is essential to protect eukaryotic cells from the accumulation of DNA damage and genome instability, a major cause of cancer and other diseases in humans. Ubiquitylation orchestrates the regulation of DDR events.Blaszczak et al. use quantitative proteomics and a reporter system based on the NanoLuc luciferase to study ubiquitylation and protein abundance changes upon genotoxic stress in yeast. The authors point out proteins that may be regulated by ubiquitylation during the DDR.