USP7HAUSP

Hydrolase that deubiquitinates target proteins such as ARMC5, FOXO4, DEPTOR, KAT5, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN, KMT2E/MLL5 and DAXX. Together with DAXX, prevents MDM2 self-ubiquitination and enhances the E3 ligase activity of MDM2 towards p53/TP53, thereby promoting p53/TP53 ubiquitination and proteasomal degradation. Deubiquitinates p53/TP53, preventing degradation of p53/TP53, and enhances p53/TP53-dependent transcription regulation, cell growth repression and apoptosis. Deubiquitinates p53/TP53 and MDM2 and strongly stabilizes p53/TP53 even in the presence of excess MDM2, and also induces p53/TP53-dependent cell growth repression and apoptosis. Deubiquitination of FOXO4 in presence of hydrogen peroxide is not dependent on p53/TP53 and inhibits FOXO4-induced transcriptional activity. In association with DAXX, is involved in the deubiquitination and translocation of PTEN from the nucleus to the cytoplasm, both processes that are counteracted by PML. Deubiquitinates KMT2E/MLL5 preventing KMT2E/MLL5 proteasomal-mediated degradation. Involved in cell proliferation during early embryonic development. Involved in transcription-coupled nucleotide excision repair (TC-NER) in response to UV damage: recruited to DNA damage sites following interaction with KIAA1530/UVSSA and promotes deubiquitination of ERCC6, preventing UV-induced degradation of ERCC6. Involved in maintenance of DNA methylation via its interaction with UHRF1 and DNMT1: acts by mediating deubiquitination of UHRF1 and DNMT1, preventing their degradation and promoting DNA methylation by DNMT1. Deubiquitinates alkylation repair enzyme ALKBH3. OTUD4 recruits USP7 and USP9X to stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions. Acts as a chromatin regulator via its association with the Polycomb group (PcG) multiprotein PRC1-like complex; may act by deubiquitinating components of the PRC1-like complex. Able to mediate deubiquitination of histone H2B; it is however unsure whether this activity takes place in vivo. Exhibits a preference towards 'Lys-48'-linked ubiquitin chains. Increases regulatory T-cells (Treg) suppressive capacity by deubiquitinating and stabilizing the transcription factor FOXP3 which is crucial for Treg cell function. Plays a role in the maintenance of the circadian clock periodicity via deubiquitination and stabilization of the CRY1 and CRY2 proteins. Deubiquitinates REST, thereby stabilizing REST and promoting the maintenance of neural progenitor cells. Deubiquitinates SIRT7, inhibiting SIRT7 histone deacetylase activity and regulating gluconeogenesis. Involved in the regulation of WASH-dependent actin polymerization at the surface of endosomes and the regulation of endosomal protein recycling. It maintains optimal WASH complex activity and precise F-actin levels via deubiquitination of TRIM27 and WASHC1. Mediates the deubiquitination of phosphorylated DEPTOR, promoting its stability and leading to decreased mTORC1 signaling. Deubiquitinates H2AB1, H2BC4 and H2BC22 (By similarity)

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(Microbial infection) Contributes to the overall stabilization and trans-activation capability of the herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110 during HSV-1 infection

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(Microbial infection) Upon infection with Epstein-Barr virus, the interaction with viral EBNA1 increases the association of USP7 with PML proteins, which is required for the polyubiquitylation and degradation of PML

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Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).

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Monomer. Homodimer. Part of a complex with DAXX, MDM2, RASSF1 and USP7. Part of a complex with DAXX, MDM2 and USP7. Interacts with MDM2; the interaction is independent of p53/TP53. Interacts with DAXX; the interaction is direct and independent of MDM2 and p53/TP53. Component of a complex composed of KMT2E/MLL5 (isoform 3), OGT (isoform 1) and USP7; the complex stabilizes KMT2E/MLL5, preventing KMT2E/MLL5 ubiquitination and proteasomal-mediated degradation. Interacts (via MATH domain) with KMT2E/MLL5 isoform 3. Interacts with OGT isoform 1. Interacts with FOXO4; the interaction is enhanced in presence of hydrogen peroxide and occurs independently of p53/TP53. Interacts with p53/TP53; the interaction is enhanced in response to DNA damage. Interacts with TSPYL5; this impairs interaction with p53/TP53. Interacts with PTEN; the interaction is direct. Interacts with ATXN1 and the strength of interaction is influenced by the length of the poly-Gln region in ATXN1. A weaker interaction seen with mutants having longer poly-Gln regions. Interacts with KIAA1530/UVSSA. Interacts with ABRAXAS2; the interaction is direct. Identified in a complex with TP53/p53 and ABRAXAS2. Interacts with MEX3C and antagonizes its ability to degrade mRNA. Interacts with DNMT1 and UHRF1. Interacts with FOXP3. Interacts (via MATH domain) with RNF220. Associated component of the Polycomb group (PcG) multiprotein PRC1-like complex. Interacts with EPOP (By similarity). Interacts with OTUD4 and USP9X; the interaction is direct. Interacts with CRY2. Interacts with REST. Interacts with ERCC6. Part of a complex consisting of USP7, MAGEL2 and TRIM27; directly interacts with MAGEL2; directly interacts with TRIM27. Interacts with FAM170A; this interaction promotes USP7 nuclear translocation and deubiquitinating activity (By similarity)

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(Microbial infection) Isoform 1 and isoform 2 interact with herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110. Binding to ICP0/VMW110 may modulate the substrate specificity or activity of USP7 to stabilize viral proteins

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(Microbial infection) Interacts with Epstein-Barr virus EBNA1; the interaction is independent and simultaneous to EBNA1 interaction with USP7 as well as necessary for PML nuclear bodies disruption by EBNA1. EBNA1, USP7 and CSNK2B form a ternary complex. EBNA1 shows a 10-fold higher affinity than p53/TP53 and can compete with it for USP7 binding

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(Microbial infection) Interacts with human cytomegalovirus proteins UL35 and UL35A; these interactions inhibit the ability of USP7 to form nuclear bodies

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(Microbial infection) Interacts with herpes virus 8/HHV-8 proteins vIRF-1 and vIRF-3; these interactions may disrupt TP53 signaling pathway during viral infection by decreasing the availability of USP7 for deubiquitinating and stabilizing TP53

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(Microbial infection) Interacts with herpes virus 8/HHV-8 protein vIRF-2; this interaction modulates antiviral signaling via disruption of USP7 interactions with innate immune signaling proteins TRAF3 and TRAF6 thus affecting their ubiquitination

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Nucleus; Cytoplasm; Nucleus, PML body; Chromosome; Present in a minority of ND10 nuclear bodies. Association with ICP0/VMW110 at early times of infection leads to an increased proportion of USP7-containing ND10. Colocalizes with ATXN1 in the nucleus. Colocalized with DAXX in speckled structures. Colocalized with PML and PTEN in promyelocytic leukemia protein (PML) nuclear bodies. Interaction with FAM170A promotes its nuclear translocation (By similarity)

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Up-regulated in regulatory T-cells (Treg). Down-regulated during neural progenitor cell differentiation

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Hao-Fountain syndrome HAFOUS An autosomal dominant neurodevelopmental disorder characterized by global developmental delay, varying degrees of intellectual disability, autism spectrum disorder, poor or absent speech, and mild facial dysmorphism. Most patients develop seizures. Additional variable features include hypotonia, hypogonadism in males, and ocular anomalies. The disease is caused by variants affecting the gene represented in this entry MIM: 616863

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