RNA-binding motif protein 39-DDB1-and-CUL4-associated factor 15 interface (RBM39-DCAF15)

The RBM39-DCAF15 interface is a therapeutic target for molecular glue degraders, such as the aryl sulfonamide Indisulam (Han et al., Science, 2017). RBM39 (RNA-binding motif protein 39), also known as CAPERalpha, is a nuclear protein essential for pre-mRNA splicing, while DCAF15 (DDB1-and-CUL4-associated factor 15) acts as a substrate receptor for the Cullin-RING E3 ubiquitin ligase 4 (CRL4) complex (Uehara et al., Nature Chemical Biology, 2017). These small molecules bind to DCAF15 and alter its surface to recruit RBM39, leading to the latter's polyubiquitination and subsequent degradation by the 26S proteasome. The depletion of RBM39 causes widespread splicing defects and cell cycle arrest, particularly in hematopoietic malignancies like acute myeloid leukemia (AML) (Assi et al., Leukemia, 2019). Clinical sensitivity to these agents is highly dependent on the expression levels of DCAF15, which serves as a key biomarker for patient selection (Nijhuis et al., Blood, 2017). This interface represents a significant advancement in targeted protein degradation, allowing for the indirect inhibition of splicing machinery in cancer cells.

Other names

RBM39-DCAF15 complexCAPERalpha-DCAF15 interfaceSulfonamide-induced RBM39-DCAF15 interactionHCC1-DCAF15 interfaceRNPC2-DCAF15 interface

Molecular glue-induced degradation: the drug binds to the DCAF15 substrate receptor of the CRL4 E3 ligase complex, creating a neo-substrate binding surface that recruits RBM39 for polyubiquitination and subsequent proteasomal degradation (Han et al., Science, 2017; Uehara et al., Nature Chemical Biology, 2017).