USP7
Description
The USP7 (ubiquitin specific peptidase 7) is a protein-coding gene located on chromosome 16.
Ubiquitin-specific-processing protease 7 (USP7), also known as ubiquitin carboxyl-terminal hydrolase 7 or herpesvirus-associated ubiquitin-specific protease (HAUSP), is an enzyme that in humans is encoded by the USP7 gene.
== Function ==
=== Regulation of the p53 tumor suppressor === USP7 or HAUSP is a ubiquitin specific protease or a deubiquitylating enzyme that cleaves ubiquitin from its substrates. Since ubiquitylation (polyubiquitination) is most commonly associated with the stability and degradation of cellular proteins, HAUSP activity generally stabilizes its substrate proteins. HAUSP is most popularly known as a direct antagonist of Mdm2, the E3 ubiquitin ligase for the tumor suppressor protein, p53. Normally, p53 levels are kept low in part due to Mdm2-mediated ubiquitylation and degradation of p53. In response to oncogenic insults, HAUSP can deubiquitinate p53 and protect p53 from Mdm2-mediated degradation, indicating that it may possess a tumor suppressor function for the immediate stabilization of p53 in response to stress. Another important role of HAUSP function involves the oncogenic stabilization of p53. Oncogenes such as Myc and E1A are thought to activate p53 through a p19 alternative reading frame (p19ARF, also called ARF)-dependent pathway, although some evidence suggests ARF is not essential in this process. A possibility is that HAUSP provides an alternative pathway for safeguarding the cell against oncogenic insults.
=== Role in transcriptional regulation === USP7 can deubiquitinate histone H2B and this activity is associated with gene silencing in Drosophila.
USP7 is a hydrolase that removes ubiquitin from target proteins, including FOXO4, DEPTOR, KAT5, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN, KMT2E/MLL5, and DAXX. It plays a crucial role in regulating various cellular processes, including:
- p53 pathway: USP7 deubiquitinates p53 and MDM2, stabilizing p53 and promoting its activity. It also enhances MDM2's E3 ligase activity toward p53, promoting p53 ubiquitination and degradation. This delicate balance between p53 stabilization and degradation influences cell growth repression and apoptosis.
- FOXO4 regulation: USP7 deubiquitinates FOXO4, inhibiting its transcriptional activity. This process is independent of p53 and is particularly relevant in the presence of hydrogen peroxide.
- PTEN localization: USP7, in association with DAXX, deubiquitinates PTEN, facilitating its translocation from the nucleus to the cytoplasm. This is counteracted by PML.
- KMT2E/MLL5 stability: USP7 deubiquitinates KMT2E/MLL5, preventing its degradation and promoting its function.
- Early embryonic development: USP7 contributes to cell proliferation during early embryonic development.
- DNA repair: USP7 is involved in transcription-coupled nucleotide excision repair (TC-NER) in response to UV damage. It interacts with KIAA1530/UVSSA, is recruited to DNA damage sites, and deubiquitinates ERCC6, preventing its degradation.
- DNA methylation: USP7 interacts with UHRF1 and DNMT1, deubiquitinates them, and prevents their degradation, promoting DNA methylation by DNMT1.
- Alkylation repair: USP7 deubiquitinates ALKBH3, an enzyme involved in alkylation repair, promoting the repair of alkylated DNA lesions. This process is facilitated by OTUD4, which recruits USP7 and USP9X to stabilize ALKBH3.
- Chromatin regulation: USP7 associates with the Polycomb group (PcG) multiprotein PRC1-like complex and may regulate chromatin by deubiquitinating components of the complex. It can also deubiquitinate histone H2B, though the in vivo relevance of this activity is unclear.
- Ubiquitin chain preference: USP7 exhibits a preference for 'Lys-48'-linked ubiquitin chains.
- Treg cell function: USP7 deubiquitinates and stabilizes FOXP3, a transcription factor crucial for the function of regulatory T-cells (Treg), enhancing their suppressive capacity.
- Circadian clock: USP7 deubiquitinates and stabilizes CRY1 and CRY2 proteins, contributing to the maintenance of the circadian clock periodicity.
- Neural progenitor cell maintenance: USP7 deubiquitinates REST, stabilizing it and promoting the maintenance of neural progenitor cells.
- Gluconeogenesis: USP7 deubiquitinates SIRT7, inhibiting its histone deacetylase activity and influencing gluconeogenesis.
- Endosomal protein recycling: USP7 regulates WASH-dependent actin polymerization at the surface of endosomes and endosomal protein recycling. It maintains optimal WASH complex activity and F-actin levels by deubiquitinating TRIM27 and WASHC1.
- mTORC1 signaling: USP7 deubiquitinates phosphorylated DEPTOR, promoting its stability and leading to decreased mTORC1 signaling.
USP7 is also known as C16DELp13.2, DEL16P13.2, HAFOUS, HAUSP, TEF1.
