The cullin-4 scaffold protein can assemble into differentially composed and highly dynamic CRL4 protein complexes that control the ubiquitin/proteasome-mediated degradation of many cellular substrate proteins. Bacher et al. (e00081-21) identify the kinase MEKK1 as a new interactor of CRL4 complexes. They further reveal the relevance of MEKK1 kinase activity for autoubiquitination of the CRL4 complex by differentially composed ubiquitin chains that contribute to DNA damage-induced degradation of CRL4 target proteins and cell survival. These data contribute to the understanding of the function of cullin-4, either as a frequently used ligand for proteolysis-targeting chimeras (PROTACs) or as a driver of tumorigenesis.