Ubiquitin-specific peptidase 15 (USP15)

Ubiquitin-specific peptidase 15 (USP15) is a member of the ubiquitin-specific protease family of deubiquitinating enzymes, located on chromosome 12q14.1. USP15 removes ubiquitin from specific protein substrates, regulating their stability, localization, and function[3]. It plays important roles in maintaining genome stability through homologous recombination-based DNA repair, positively regulating BRCA1/BARD1 retention at DNA double-strand breaks[1]. USP15 controls the turnover of numerous proteins involved in cancer-associated pathways, including ERα, MDM2, p53, and TGF-β receptor I, with context-dependent tumor-promoting or tumor-suppressive effects[2][3]. Alterations in USP15 expression or function are implicated in cancer, neurodegenerative diseases, and other pathological states, making it a potential therapeutic target and biomarker for treatment selection, particularly in cancers sensitive to DNA repair pathway modulation[1][2][3]. However, due to its central role in essential cellular processes, therapeutic targeting may carry significant safety and selectivity challenges[3].

Other names

Ubiquitin carboxyl-terminal hydrolase 15KIAA0529UNPH4Deubiquitinating enzyme 15Ubiquitin thioesterase 15Ubiquitin-specific-processing protease 15Unph-2Unph4

Drugs targeting defects in DNA damage repair (such as PARP inhibitors) can act synergistically or show increased efficacy in the context of USP15 mutation/loss[1]. Proposed mechanism for research-stage USP15 inhibitors: inhibit deubiquitination activity, leading to destabilization of USP15 substrates[2].