E3 ubiquitin-protein ligase COP1 (COP1)

E3 ubiquitin-protein ligase COP1, also known as RFWD2, is a critical enzyme that regulates protein stability through the ubiquitin-proteasome system. It functions as a substrate-specific adaptor within the Cullin-RING ligase 4 (CRL4) complex, targeting various transcription factors and signaling proteins for degradation. Key substrates include the tumor suppressor p53, oncogenic ETS family members (ETV1, ETV4, ETV5), and metabolic regulators like ACSL4 and FOXO4. In many cancers, such as breast, ovarian, and hepatocellular carcinoma, COP1 is overexpressed and acts as an oncogene by promoting the degradation of p53. Conversely, in other contexts like melanoma, its loss can lead to the stabilization of ETS factors, conferring resistance to MAPK pathway inhibitors. Recent research also highlights its role in the tumor microenvironment, where it modulates macrophage infiltration and immune evasion. While no COP1-targeted therapies are currently FDA-approved, it is an active area of drug discovery, with efforts focusing on small-molecule inhibitors of its WD40 domain and the development of PROTACs to harness its ligase activity for targeted protein degradation.

Other names

RFWD2Constitutive photomorphogenesis protein 1 homologRING finger and WD repeat-containing protein 2RNF200CFAP78FAP78hCOP1

Inhibition of COP1-mediated ubiquitination to stabilize tumor suppressors (e.g., p53, ACSL4) or prevent degradation of immune-modulating factors (e.g., C/EBPδ); alternatively, recruitment of COP1 for targeted protein degradation via PROTACs.