UBE2M transfers NEDD8 to lysine 705 of CUL4A and lysine 859 of CUL4B (Hori et al, 1999; Duda et al, 2008). Neddylation increases the ubiquitination activity of the E3 complex towards its targets, and prevents binding of the CUL4 complex with the CAND1 inhibitor (Hori et al, 1999; Duda et al, 2008). CRL4 complexes ubiquitinate target proteins involved in processes such as cell cycle progression, DNA repair and replication, cell growth and metabolism (reviewed in Hannah and Zhou, 2015; Sang et al, 2015). CRL4 complexes are also hijacked by a number of viruses, redirecting the ubiquitin ligase complex to target host proteins and in this way promoting viral propagation (reveiwed in Mahon et al, 2014). Note that because many of the key CRL4 ubiquitin targets are nuclear, these complexes are depicted in the nucleus. Cytoplasmic targets have also been identified, however (reviewed in Hannah and Zhou, 2015).