Cullin-RING E3 ligases (CRLs) are the largest known family of ubiquitin ligases. The activity of some CRLs is inhibited by an eight-subunit complex known as the COP9 signalosome, which can act on the cullin subunit of CRLs and thereby influence the ubiquitylation of CRL substrates. On p. 1035, Lionel Pintard and colleagues use mass spectrometry to identify the subset of CRLs that might be regulated by the COP9 signalosome. By determining the adaptor proteins with which six of the COP9-signalosome subunits interact, the authors identify 15 CRLs that associate with the COP9 signalosome. Interestingly, most of these CRLs have a role in DNA metabolism; the authors propose that their coordinated regulation might ensure rapid CRL-mediated responses to specific physiological cues. The authors' mass spectrometry analysis also reveals that Dda1, a small protein that is thought to associate with CRL4 complexes, positively regulates their ubiquitin-ligase activity. Interestingly, the expression of Dda1 and its association with chromatin occurs in a cell-cycle-dependent manner, and the authors speculate that Dda1 might regulate the function of CRL4 complexes that have a role in DNA replication and repair.