RNA-binding motif protein 39–DDB1-and-CUL4-associated factor 15 E3 ligase complex (RBM39–DCAF15 complex)

The RBM39–DCAF15 E3 ligase complex is a molecular assembly that has gained significant attention as a target for 'molecular glue' degraders, specifically aryl sulfonamides like Indisulam. RBM39 (RNA-binding motif protein 39) is an essential splicing factor that regulates the processing of pre-mRNAs involved in cell cycle progression and DNA repair. DCAF15 (DDB1-and-CUL4-associated factor 15) acts as a substrate recognition component of the Cullin-RING ligase 4 (CRL4) complex. Under normal physiological conditions, DCAF15 does not interact with RBM39; however, the presence of certain sulfonamide drugs facilitates a gain-of-function interaction between the two. (Han et al., 2017, Science; Uehara et al., 2017, Nature Chemical Biology). This induced proximity leads to the polyubiquitination of RBM39 by the CRL4-DCAF15 machinery, resulting in its rapid degradation by the 26S proteasome. The depletion of RBM39 causes widespread alternative splicing errors, leading to the production of non-functional transcripts and subsequent apoptosis in sensitive cancer cells. This mechanism is particularly effective in hematopoietic malignancies where DCAF15 is highly expressed, making it a primary biomarker for drug sensitivity. (Nishimura et al., 2020, Nature Communications; UniProt Q14498, Q66K15). The complex represents a paradigm for targeted protein degradation where a small molecule redefines the substrate specificity of an E3 ligase to eliminate a previously 'undruggable' RNA-binding protein.

Other names

RBM39-DCAF15-CRL4 complexCAPERalpha-DCAF15 complexIndisulam-DCAF15-RBM39 complexSulfonamide-induced RBM39-DCAF15 complex

Molecular glue degradation; the drug binds to the DCAF15 substrate receptor of the CRL4 E3 ligase complex, creating a neo-interface that recruits RBM39 for polyubiquitination and subsequent proteasomal degradation.