Nature Structural & Molecular Biology, Published online: 08 September 2025; doi:10.1038/s41594-025-01651-0Post-translational modifications show mechanistic crosstalk, exemplified by the ADP-ribose–ubiquitin hybrid signal, in which one post-translational modification modifies another. This Comment highlights its discovery, mechanistic basis and functional consequences, and outlines critical questions for understanding this emerging signaling paradigm.

Deltex E3s modify ADP-ribosylated targets with ubiquitin, creating a hybrid modification whose readers remains unknown. Here, the authors synthesise a non-hydrolysable probe that mimics the modificati...