DCAF5 (DDB1 and CUL4 associated factor 5) functions as a substrate receptor for the CUL4-DDB1 E3 ubiquitin-protein ligase complex (CRL4), mediating ubiquitination of methylated non-histone proteins including SOX2, DNMT1, and E2F1 12. The CRL4-DCAF5 complex recognizes methylated lysine residues through interaction with L3MBTL3, a methyl-binding protein, to target substrates for proteasomal degradation 123. This mechanism regulates stem cell self-renewal and pluripotency; for example, knockdown of DCAF5 stabilizes SOX2 protein and rescues embryonic stem cell defects 2. DCAF5 also performs quality-control functions for SWI/SNF chr14-remodeling complexes, promoting degradation of incompletely assembled complexes 4. Therapeutically, DCAF5 inhibition suppresses SMARCB1-mutant cancers by allowing reaccumulation of SWI/SNF complexes and restoration of tumor-suppressor function in vivo 4. Disease associations include potential involvement in congenital heart defects and intellectual disability through haploinsufficiency 5, and rare genetic variants associated with neuropeptide Y autoantibodies in type 1 diabetes 6. These findings establish DCAF5 as a critical regulator of protein stability and a potential therapeutic target in cancer.