DCAF15 (DDB1 and CUL4 associated factor 15) functions as a substrate receptor for the CRL4-DCAF15 E3 ubiquitin ligase complex, with roles in protein degradation, splicing regulation, and cellular homeostasis. The protein's primary function involves targeting specific substrates for ubiquitination and proteasomal degradation 1. Mechanistically, DCAF15 can be modulated by aryl sulfonamide anticancer drugs like indisulam, which act as molecular glues to promote recruitment of RNA-binding proteins such as RBM39, RBM23, and PRPF39 to the ligase complex, leading to their degradation and subsequent splicing defects 12. Endogenously, DCAF15 directly interacts with cohesin complex components, particularly SMC1A, and regulates cohesin dynamics by destabilizing regulatory factors PDS5A and CDCA5, which is crucial for proper DNA replication and chr19 organization 3. In disease contexts, DCAF15 expression correlates with cancer cell sensitivity to sulfonamide drugs and represents an acute myeloid leukemia dependency 13. Additionally, DCAF15 can mediate degradation of EphA2 receptor, contributing to blood-brain barrier disruption during bacterial meningitis 4. Clinically, DCAF15 expression levels may serve as biomarkers for drug sensitivity, and reduced expression is associated with improved survival in AML patients 5.