Ubiquitin-specific peptidase 16 (USP16)

Ubiquitin-specific peptidase 16 (USP16) is a zinc finger-containing deubiquitinating enzyme primarily recognized for removing ubiquitin from histone H2A, thereby regulating gene expression through antagonism of Polycomb Repressive Complex 1 (PRC1) activity[1][2][3]. USP16 is phosphorylated upon entry into mitosis and dephosphorylated during the metaphase–anaphase transition, suggesting dynamic regulation during the cell cycle[1][3]. In addition to its nuclear functions, where it is critical for chromatin remodeling and transcriptional activation, USP16 also acts in the cytoplasm on substrates involved in ribosome biogenesis and immune signaling[1][4]. USP16 is involved in diverse biological processes such as stem cell self-renewal, DNA damage repair, immune cell activation, and cell fate determination[1][2][4]. Dysfunction or dysregulation of USP16 is connected to oncogenesis, immune diseases, arteries, and reproductive health, making USP16 a potential—but currently undrugged—therapeutic target[1][2][3]. No approved drugs or clinical inhibitors directly targeting USP16 exist as of September 2025.

Other names

Ubiquitin carboxyl-terminal hydrolase 16MSTP039Ubp-MDeubiquitinating enzyme 16Ubiquitin thioesterase 16Ubiquitin-processing protease UBP-MUBP-MUBPMubiquitin carboxyl-terminal hydrolase 16deubiquitinating enzyme 16ubiquitin specific protease 16ubiquitin thioesterase 16ubiquitin thiolesterase 16ubiquitin-processing protease UBP-Mubiquitin-specific processing protease 16

Inhibition of deubiquitination activity (potential, by small-molecule inhibitors or activators; no specific drugs currently in clinical use or research as direct USP16 inhibitors are publicly characterized)