Cullin-RING E3 ubiquitin ligase CRL4 complex (CRL4)

The **Cullin-RING E3 ubiquitin ligase CRL4 complex** is a multisubunit E3 ubiquitin ligase within the largest family of cullin-RING ligases (CRLs) in eukaryotes, comprising a cullin scaffold (CUL4A or CUL4B), the adaptor protein DDB1, substrate receptors known as DDB1-CUL4-associated factors (DCAFs), and the RING finger protein RBX1/ROC1. This architecture enables CRL4 to ubiquitinate diverse substrates for proteasomal degradation, regulating critical processes such as cell cycle progression (e.g., degradation of cyclin E, p27, Cdt1), DNA damage repair, nucleotide excision repair, chromatin remodeling, and signal transduction pathways including EGFR-AKT, mTOR, Wnt/β-catenin, and others. CRL4 achieves substrate specificity through DCAFs like CDT2, VprBP, and CRBN, often recognizing degrons such as PIP boxes in a PCNA-dependent manner during DNA replication. Dysregulation of CRL4, via overexpression of CUL4A/B or altered substrate turnover, promotes oncogenesis by destabilizing tumor suppressors (e.g., p16, PTEN, TSC2, merlin) and stabilizing oncoproteins (e.g., cyclin E, β-catenin, c-Myc, c-Jun). In cancer, CRL4 is implicated in proliferation, invasion, genomic instability, and resistance to apoptosis, with elevated expression in hepatocellular carcinoma, non-small cell lung cancer, and other malignancies. Therapeutic targeting exploits CRL4's role in protein degradation; small-molecule inhibitors like KH-4-43 bind the core complex to block ubiquitination of substrates such as CK1α and CDT1, while CRL4^CRBN is hijacked by immunomodulatory drugs (e.g., thalidomide analogs) for neo-substrate degradation in multiple myeloma treatment.

Other names

CRL4 E3 ubiquitin ligaseCUL4-RING E3 ligasecullin4-RING E3 ubiquitin ligase

Inhibition of ubiquitin ligase activity, Stabilization of substrates like CDT1 and CK1α