USP7
Encyclopedia
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
.
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 acitivity 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. Interestingly, 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. An intriguing possibility is that HAUSP provides an alternative pathway for safeguarding the cell against oncogenic insults.
and this activity is associated with gene silencing in Drosophila. USP7 associates with a metabolic enzyme, GMP synthetase (GMPS) and this association stimulates USP7 deubiquitinase activity towards H2B
. The USP7-GMPS complex is recruited to the polycomb (Pc) region in Drosophila and contributes to epigenetic silecing of homeotic
genes.
(HSV
), hence the name Herpesvirus Associated USP (HAUSP). ICP0 is an E3-ubiquitin ligase that is involved in ubiquitination and subsequent degradation of itself and certain cellular proteins. USP7 has been shown to regulate the auto-ubiquitination and degradation of ICP0.
More recently, an interaction between USP7 and the EBNA1 protein of Epstein-Barr virus
(EBV) (another herpesvirus) was also discovered. This interaction is particularly interesting given the oncogenic potential (potential to cause cancer) of EBV, which is associated with several human cancers. EBNA1 can compete with p53 for binding USP7. Stabilization by USP7 is important for the tumor suppressor function of p53. In cells, EBNA1 can sequester USP7 from p53 and thus attenuate stabilization of p53, rendering the cells predisposed to turning cancerous. Compromising the function of p53 by sequestering USP7 is one way EBNA1 can contribute to the oncogenic potential of EBV. Additionally, human USP7 was also shown to form a complex with GMPS and this complex is recruited to EBV genome sequences. USP7 was shown to be important for histone H2B
deubiquitination in human cells and for deubiquitination of histone H2B
incorporated in the EBV genome. Thus USP7 may also be important for regulation of viral gene expression.
The fact that viral proteins have evolved so as to target USP7, underscores the significance of USP7 in tumor suppression and other cellular processes.
with Ataxin 1
, CLSPN
and P53
. A proteomic screen conducted to identify interacting partners of 75 human deubiquitinating enzymes (DUBs) has revealed several novel binding partners of USP7.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that in humans is encoded by the USP7 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Regulation of the p53 tumor suppressor
USP7 or HAUSP is a ubiquitinUbiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
specific protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
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 acitivity generally stabilizes its substrate proteins. HAUSP is most popularly known as a direct antagonist of Mdm2
Mdm2
Mdm2 is an important negative regulator of the p53 tumor suppressor. It is the name of a gene as well as the protein encoded by that gene. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain of the p53 tumor suppressor and an inhibitor of...
, the E3 ubiquitin ligase
Ubiquitin ligase
A ubiquitin ligase is a protein that in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome...
for the tumor suppressor protein, p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
. Normally, p53 levels are kept low in part due to Mdm2-mediated ubiquitylation and degradation of p53. Interestingly, 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
Myc
Myc is a regulator gene that codes for a transcription factor. In the human genome, Myc is located on chromosome 8 and is believed to regulate expression of 15% of all genes through binding on Enhancer Box sequences and recruiting histone acetyltransferases...
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. An intriguing possibility is that HAUSP provides an alternative pathway for safeguarding the cell against oncogenic insults.
Role in transcriptional regulation
USP7 can deubiquitinate histone H2BHistone H2B
Histone H2B is one of the 5 main histone proteins involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N terminal tail H2B is involved with the structure of the nucleosomes of the 'beads on a string' structure.See nucleosome, histone and...
and this activity is associated with gene silencing in Drosophila. USP7 associates with a metabolic enzyme, GMP synthetase (GMPS) and this association stimulates USP7 deubiquitinase activity towards H2B
Histone H2B
Histone H2B is one of the 5 main histone proteins involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N terminal tail H2B is involved with the structure of the nucleosomes of the 'beads on a string' structure.See nucleosome, histone and...
. The USP7-GMPS complex is recruited to the polycomb (Pc) region in Drosophila and contributes to epigenetic silecing of homeotic
Homeotic gene
Hox genes are a group of related genes that determine the basic structure and orientation of an organism.Hox genes are critical for the proper placement of segment structures of animals during early embryonic development Hox genes are a group of related genes that determine the basic structure and...
genes.
Association with herpesviruses
USP7 was originally identified as a protein associated with the ICP0 protein of herpes simplex virusHerpes simplex virus
Herpes simplex virus 1 and 2 , also known as Human herpes virus 1 and 2 , are two members of the herpes virus family, Herpesviridae, that infect humans. Both HSV-1 and HSV-2 are ubiquitous and contagious...
(HSV
HSV
HSV may refer to:* Herpes simplex virus* HSV color space * HSV television station, the Melbourne station of Australia's Seven television network...
), hence the name Herpesvirus Associated USP (HAUSP). ICP0 is an E3-ubiquitin ligase that is involved in ubiquitination and subsequent degradation of itself and certain cellular proteins. USP7 has been shown to regulate the auto-ubiquitination and degradation of ICP0.
More recently, an interaction between USP7 and the EBNA1 protein of Epstein-Barr virus
Epstein-Barr virus
The Epstein–Barr virus , also called human herpesvirus 4 , is a virus of the herpes family and is one of the most common viruses in humans. It is best known as the cause of infectious mononucleosis...
(EBV) (another herpesvirus) was also discovered. This interaction is particularly interesting given the oncogenic potential (potential to cause cancer) of EBV, which is associated with several human cancers. EBNA1 can compete with p53 for binding USP7. Stabilization by USP7 is important for the tumor suppressor function of p53. In cells, EBNA1 can sequester USP7 from p53 and thus attenuate stabilization of p53, rendering the cells predisposed to turning cancerous. Compromising the function of p53 by sequestering USP7 is one way EBNA1 can contribute to the oncogenic potential of EBV. Additionally, human USP7 was also shown to form a complex with GMPS and this complex is recruited to EBV genome sequences. USP7 was shown to be important for histone H2B
Histone H2B
Histone H2B is one of the 5 main histone proteins involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N terminal tail H2B is involved with the structure of the nucleosomes of the 'beads on a string' structure.See nucleosome, histone and...
deubiquitination in human cells and for deubiquitination of histone H2B
Histone H2B
Histone H2B is one of the 5 main histone proteins involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N terminal tail H2B is involved with the structure of the nucleosomes of the 'beads on a string' structure.See nucleosome, histone and...
incorporated in the EBV genome. Thus USP7 may also be important for regulation of viral gene expression.
The fact that viral proteins have evolved so as to target USP7, underscores the significance of USP7 in tumor suppression and other cellular processes.
Binding partners
The following is a list of some of the known cellular binding partners of USP7/HAUSP:- p53P53p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
- Mdm2Mdm2Mdm2 is an important negative regulator of the p53 tumor suppressor. It is the name of a gene as well as the protein encoded by that gene. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain of the p53 tumor suppressor and an inhibitor of...
- Mdm4MDM4Protein Mdm4 is a protein that in humans is encoded by the MDM4 gene.-Interactions:MDM4 has been shown to interact with E2F1, Mdm2 and P53.-Further reading:...
/MdmX - FOXO4FOXO4Forkhead box protein O4 is a protein that in humans is encoded by the FOXO4 gene.-Interactions:FOXO4 has been shown to interact with PIN1 and Mdm2.-Further reading:...
- DaxxDeath associated protein 6Death-associated protein 6 also known as DAXX is a protein that in humans is encoded by the DAXX gene.- Function :DAXX, a death-domain-associated protein, was first discovered through its cytoplasmic interaction with the classical death receptor Fas...
- PTENPTEN (gene)Phosphatase and tensin homolog is a protein that, in humans, is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers....
- March7MARCH7E3 ubiquitin-protein ligase MARCH7 is an enzyme that in humans is encoded by the MARCH7 gene.-Further reading:...
Interactions
USP7 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with Ataxin 1
Ataxin 1
Ataxin-1 is a protein that in humans is encoded by the ATXN1 gene.-Interactions:Ataxin 1 has been shown to interact with Glyceraldehyde 3-phosphate dehydrogenase, Coilin, USP7 and UBE2E1.-External links:*...
, CLSPN
CLSPN
Claspin is a protein that in humans is encoded by the CLSPN gene.-Interactions:CLSPN has been shown to interact with USP7, CHEK1 and BRCA1.-Further reading:...
and P53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
. A proteomic screen conducted to identify interacting partners of 75 human deubiquitinating enzymes (DUBs) has revealed several novel binding partners of USP7.