RNA-binding motif protein 39 (RBM39) (RBM39)

RNA-binding motif protein 39 (RBM39) is a nuclear RNA-binding protein that functions as a splicing factor and a transcriptional coactivator for various transcription factors, including AP-1 and estrogen receptors (UniProt Q14498). It plays a vital role in maintaining the fidelity of the transcriptome in cancer cells, particularly in myeloid leukemias and certain solid tumors (Han et al., 2017, Science). RBM39 has gained significant attention as a target for "molecular glue" degraders, specifically aryl sulfonamides like Indisulam and E7820. These small molecules bridge the interaction between the RRM2 domain of RBM39 and the DCAF15 substrate receptor of the CUL4-DDB1 E3 ubiquitin ligase complex (Uehara et al., 2017, Nat Chem Biol). This drug-induced proximity leads to the polyubiquitination and subsequent proteasomal degradation of RBM39. The depletion of RBM39 causes massive alternative splicing defects and the induction of lethal mis-splicing events, leading to cell cycle arrest and apoptosis. Clinical sensitivity to RBM39 degraders is primarily determined by the expression levels of DCAF15, which acts as a predictive biomarker for patient selection.

Other names

CAPERalphaHCC1RNPC2RNA-binding motif protein 39Coactivator of activating protein-1 and estrogen receptors

Molecular glue-induced recruitment of RBM39 to the DCAF15-CUL4 E3 ligase complex, leading to its polyubiquitination and proteasomal degradation