Ubiquitin C-terminal hydrolase 7

USP7 (ubiquitin carboxyl-terminal hydrolase 7) is a deubiquitinating enzyme that removes ubiquitin modifications from numerous substrates, including p53, MDM2, FOXO4, PTEN, DNA repair proteins, and chromatin regulators (UniProt: Q93009). It plays central roles in p53 stability and transcriptional activity, DNA damage response, DNA methylation maintenance, and immune regulation via FOXP3 stabilization. USP7 is also implicated in circadian rhythm maintenance and endosomal protein recycling.

Germline mutations in USP7 cause Hao-Fountain syndrome, an autosomal dominant neurodevelopmental disorder featuring intellectual disability, autism spectrum disorder, seizures, and developmental delay (UniProt: Q93009). The protein's broad involvement in cell proliferation, transcriptional control, and DNA homeostasis underscores its fundamental cellular roles.

In Alzheimer's disease, USP7 is significantly downregulated in post-mortem human brain tissue compared to age-matched controls (mean log2 fold-change: −1.03; Chaparral AD proteomics). This reduction may impair deubiquitination-dependent stabilization of substrates critical for neuronal function, potentially contributing to AD-related neurodegeneration and protein quality control dysfunction.