Cullin-RING E3 ubiquitin ligase 4 (CRL4)

The **Cullin-RING E3 ubiquitin ligase 4 (CRL4)** is a modular multi-protein enzyme complex that directs specific target proteins for ubiquitination, which marks them for degradation by the proteasome[1][2][3]. The core complex consists of the scaffold protein CUL4A or CUL4B, the adaptor DDB1, a variable WD40 domain-containing substrate receptor (often called DCAF), and the RING finger protein ROC1/RBX1[1][3]. CRL4 complexes regulate cell cycle progression, DNA repair, and chromatin remodeling, with dysregulation implicated in various cancers and viral pathologies[1][2][4]. Small-molecule inhibitors such as 33-11 and KH-4-43 directly target the core ligase and show promising anticancer activity, especially in tumor models with specific vulnerability conferred by low CUL4 expression[1][2]. However, as ubiquitination is a broadly essential process, systemic inhibition of CRL4 poses significant safety and toxicity challenges.

Other names

CRL4CUL4-RING E3 ligaseCUL4 E3 ubiquitin ligaseCullin 4 E3 ligaseCUL4A/B-DDB1 complex

Inhibition of CRL4-mediated ubiquitination, leading to stabilization of substrates (e.g., CDT1), triggering apoptosis, especially in tumor cells with low CUL4 expression; Modulation of substrate receptor binding; Interference with enzyme-substrate or enzyme-adaptor protein interfaces