DDB1- and CUL4-associated factor 15 ubiquitin ligase complex (DCAF15 ubiquitin ligase complex)

The **DDB1– and CUL4–associated factor 15 ubiquitin ligase complex** is a multi-protein E3 ubiquitin-protein ligase that mediates the transfer of ubiquitin to specific substrate proteins, targeting them for proteasomal degradation. The core components include DCAF15, damaged DNA binding protein 1 (DDB1), DET1 and DDB1 associated protein 1 (DDA1), and cullin 4. This complex plays a regulatory role in natural killer cell effector functions by mediating the degradation of target proteins such as cohesin subunits SMC1A and SMC3. In cancer biology—particularly acute myeloid leukemia—the endogenous function of this complex involves sustaining malignant proliferation through post-translational regulation of cohesin dynamics; loss or inhibition leads to impaired DNA replication integrity, increased DNA damage, defective chromatin organization, apoptosis, and heightened sensitivity to replication stress-inducing agents. Pharmacologically relevant aryl sulfonamide drugs such as indisulam or E7820 act as molecular glues that alter the substrate specificity of the DCAF15 E3 ligase. These drugs promote interaction between weakly binding substrates like splicing factors RBM39 with the DCX(DCAF15) complex—resulting in their polyubiquitination and subsequent proteasomal degradation. This mechanism underlies their anti-cancer activity by inducing splicing defects that are lethal to certain cancer cells. The physiological roles extend beyond cancer biology into immune regulation via effects on antigen-presenting cells' interactions with NK cells. The full spectrum of safety concerns or biomarker utility remains under investigation.[1][2][3]

Other names

DCAF15 E3 ubiquitin ligase complexDCX(DCAF15) complexC19orf72 (previous gene symbol)DDB1 and CUL4 associated factor 15[2][4]

Molecular glue-induced recruitment of neo-substrates, leading to their ubiquitination and proteasomal degradation (e.g., RBM39, RBM23, PRPF39)[2][3]