DDB1- and CUL4-associated factor 1 (DCAF1) (DCAF1)

DDB1- and CUL4-associated factor 1 (DCAF1), also known as VprBP, is a multi-functional protein that serves as a substrate recognition component of the CRL4 (Cullin-4-RING) E3 ubiquitin ligase complex and possesses intrinsic protein kinase activity [1, 2]. The protein's C-terminal region contains an atypical kinase domain responsible for the phosphorylation of histone H2A at Thr120 (H2AT120ph), a modification crucial for chromatin signaling and cell cycle regulation [2, 3]. DCAF1 is a key target for viral proteins, most notably the HIV-1 Vpr protein, which hijacks the CRL4-DCAF1 complex to induce cell cycle arrest and degrade host cellular targets [4, 5]. In oncology, DCAF1 is frequently overexpressed and promotes tumor growth by regulating the stability of tumor suppressors like p53 and Merlin (NF2) [6, 7]. The kinase domain of DCAF1 is particularly notable for its atypical structure, lacking the classical sequence motifs of the eukaryotic protein kinase superfamily while maintaining catalytic efficiency [2]. Recent drug discovery efforts have focused on DCAF1 both as a direct therapeutic target for its kinase and ligase activities and as a recruitment module for proteolysis-targeting chimeras (PROTACs) due to its broad tissue expression and efficient protein degradation capabilities [8, 9].

Other names

Vpr-binding proteinVprBPDDB1- and CUL4-associated factor 1RIPDCAF1

Inhibition of atypical kinase activity to prevent histone H2A phosphorylation and recruitment of neo-substrates to the CRL4-DCAF1 E3 ligase complex for proteasomal degradation