Cullin-4-DNA damage-binding protein 1 E3 ubiquitin ligase complex (CRL4)

The Cullin-4-DNA damage-binding protein 1 (CUL4-DDB1) E3 ubiquitin ligase complex, commonly known as CRL4, is a multi-protein assembly that regulates protein stability through the ubiquitin-proteasome system [1]. It consists of a Cullin-4 scaffold (CUL4A or CUL4B), the RING-finger protein RBX1, and the adaptor protein DDB1, which recruits various substrate receptors called DDB1-and-Cullin-4-associated factors (DCAFs) [2, 3]. This complex is essential for maintaining genomic integrity, managing the DNA damage response, and controlling cell cycle progression [1]. In clinical oncology, the CRL4 complex is the primary target of immunomodulatory imide drugs (IMiDs) like lenalidomide, which bind to the DCAF Cereblon (CRBN) to induce the degradation of neo-substrates such as Ikaros and Aiolos [4]. Furthermore, the CRL4-CRBN axis is a cornerstone of targeted protein degradation (TPD) technology, serving as the E3 ligase component for numerous Proteolysis-Targeting Chimeras (PROTACs) [5]. Dysregulation of this complex is linked to various cancers and is often exploited by viral pathogens to evade the host immune system [1, 3]. Citations: [1] Angers, S., et al. (2006) Nature, PMID: 16964240; [2] Jackson, S., & Eldridge, A. G. (2002) Mol Cell, PMID: 11792314; [3] Lee, J., & Zhou, P. (2007) Mol Cell, PMID: 17488654; [4] Ito, T., et al. (2010) Science, PMID: 20228806; [5] Bondeson, D. P., et al. (2015) Nat Chem Biol, PMID: 26030734.

Other names

CRL4 complexCUL4-DDB1-RBX1 complexCUL4-DDB1-ROC1 complexCullin-4-RING ligase

Molecular glue-induced degradation of neo-substrates, E3 ubiquitin ligase recruitment for targeted protein degradation (TPD)