USP39

USP39 (Ubiquitin-Specific Peptidase 39), also termed hPrp8 or 39 kDa ubiquitin-specific protease, is a deubiquitinating enzyme (DUB)-like protein lacking catalytic activity due to critical residue substitutions in its USP domain. Functionally, it serves as a scaffold component of the U5 snRNP complex, playing an essential role in pre-mRNA splicing by stabilizing spliceosome assembly and regulating splice site selection. USP39 is implicated in the ATM/ATR-mediated DNA damage response pathway and modulates cell cycle progression, particularly at the G2/M checkpoint. Dysregulation of USP39 correlates with tumorigenesis, including hepatocellular carcinoma, glioblastoma, and colorectal cancer, through aberrant splicing of oncogenes/tumor suppressors (e.g., BCL2L1, MDM2). It also associates with neurological disorders such as spinal muscular atrophy via SMN2 splicing defects. Despite its therapeutic potential, no direct USP39 inhibitors have reached clinical trials. Current strategies focus on antisense oligonucleotides (ASOs) targeting USP39-dependent splicing events, with preclinical studies showing efficacy in spliceopathy-linked cancers. Its dual roles in splicing fidelity and genome stability make it a challenging yet compelling target for precision oncology.