DCAF1

DCAF1 (Ddb1-Cullin4-associated factor 1) serves as a substrate receptor for both CRL4 and EDVP E3 ubiquitin ligases, regulating protein degradation in multiple cellular contexts^[1][2]. Mechanistically, DCAF1 recruits specific targets through its WD40 domain, mediating ubiquitination of substrates such as UNG2, PP2A-A, and transcriptional regulators ZIP and sZIP^[3][4][5][6]. DCAF1 controls T-cell activation, growth, and proliferation through p53-dependent and independent pathways, and is essential for immune homeostasis and T-cell responses during viral infections^[7][8]. In hepatocellular carcinoma models, DCAF1 interacts with PARD3 to activate Akt signaling, promoting tumor progression and metastasis, highlighting its oncogenic potential^[9]. Compared with related isoforms, DCAF1 contains a unique LisH-mediated oligomerization region, enabling dimerization of the CRL4-DCAF1 complex, which enhances its E3 ligase activity^[3]. In reproductive biology, DCAF1 mediates oocyte meiotic maturation via poly-ubiquitination of PP2A-A, demonstrating substrate-specific roles in developmental pathways^[5]. DCAF1 is also a target for HIV-1 Vpr, which hijacks the DCAF1-containing CRL4 complex to induce G2 cell cycle arrest and degrade host restriction factors, illustrating its viral exploitation^{[10][11][12][13][14]}. Recent chemical biology studies have identified small-molecule ligands and PROTACs targeting DCAF1, enabling controlled protein degradation and functional interrogation in cancer and immune cells^{[15][16][17][12][2]}.