Post-translational modifications (PTMs) can regulate the localization, function, and activity of proteins. Different PTMs can influence each other to create complex regulatory networks with significant implications for cellular signaling and protein homeostasis; an interplay known as crosstalk. Here, we highlight recent studies revealing crosstalk between ubiquitination and ADP-ribosylation, two PTMs that, while chemically distinct, share notable mechanistic similarities. We discuss how their enzymes, substrates, and resulting adducts are similar and distinct. We describe the different levels at which one PTM impacts the other and, ultimately, how they build on each other to create a hybrid modification. Both ADP-ribosylation and ubiquitination are targeted by drugs, and understanding this crosstalk is also important for translational research, opening potentially innovative strategies for new therapies.
Vela-Rodríguez et al. (Sun,) studied this question.