
Deubiquitinating enzymes (DUBs), also known as deubiquitinating peptidases, deubiquitinating isopeptidases, deubiquitinases, ubiquitin proteases, ubiquitin hydrolases, or ubiquitin isopeptidases, are a large group of
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...
s that cleave
ubiquitin
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 19 ...
from proteins.
Ubiquitin is attached to proteins in order to regulate the degradation of proteins via the
proteasome
Proteasomes are essential protein complexes responsible for the degradation of proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are found inside all e ...
and
lysosome
A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...
; coordinate the
cellular localisation of proteins; activate and inactivate proteins; and modulate
protein-protein interactions.
DUBs can reverse these effects by cleaving the peptide or isopeptide bond between ubiquitin and its substrate protein. In humans there are nearly 100 DUB genes, which can be classified into two main classes:
cysteine protease
Cysteine proteases, also known as thiol proteases, are hydrolase enzymes that degrade proteins. These proteases share a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic triad or dyad.
Discovered by Gopal Chu ...
s and
metalloprotease
A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myoge ...
s. The cysteine proteases comprise ubiquitin-specific proteases (USPs), ubiquitin C-terminal hydrolases (UCHs), Machado-Josephin domain proteases (MJDs) and ovarian tumour proteases (OTU). The metalloprotease group contains only the Jab1/Mov34/Mpr1 Pad1 N-terminal+ (MPN+) (JAMM) domain proteases.
Classes
In humans there are 102 putative DUB genes, which can be classified into two main classes:
cysteine protease
Cysteine proteases, also known as thiol proteases, are hydrolase enzymes that degrade proteins. These proteases share a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic triad or dyad.
Discovered by Gopal Chu ...
s and
metalloprotease
A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myoge ...
s, consisting of 58 ubiquitin-specific proteases (USPs), 4 ubiquitin C-terminal hydrolases (UCHs), 5 Machado-Josephin domain proteases (MJDs), 14 ovarian tumour proteases (OTU), and 14 Jab1/Mov34/Mpr1 Pad1 N-terminal+ (MPN+) (JAMM) domain-containing genes. 11 of these proteins are predicted to be non-functional, leaving 79 functional enzymes.
In yeast, the USPs are known as ubiquitin-specific-processing proteases (UBPs).
Cysteine proteases
There are six main superfamilies of cysteine protease DUBs:
* the ubiquitin-specific protease (USP/UBP) superfamily; (
USP1,
USP2,
USP3,
USP4,
USP5,
USP6
Ubiquitin carboxyl-terminal hydrolase 6 (USB6), also termed TRE17 and Tre-2, is a deubiquitinating enzyme that in humans is encoded by the hominid (i.e. found only in primates) ''USP6'' gene located at band 13.2 on the short (i.e. "p") arm of ch ...
,
USP7
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
Regul ...
,
USP8
Ubiquitin carboxyl-terminal hydrolase 8 is an enzyme that in humans is encoded by the ''USP8'' gene.
Interactions
USP8 has been shown to interact with RNF41 and STAM2
Signal transducing adapter molecule 2 is a protein that in humans is enc ...
,
USP9X
Probable ubiquitin carboxyl-terminal hydrolase FAF-X is an enzyme that in humans is encoded by the ''USP9X'' gene.
Function
This gene is a member of the peptidase C19 family and encodes a protein that is similar to ubiquitin-specific protease ...
,
USP9Y,
USP10
Ubiquitin specific peptidase 10, also known as USP10, is an enzyme which in humans is encoded by the ''USP10'' gene.
Function
Ubiquitin is a highly conserved protein that is covalently linked to other proteins to regulate their function and de ...
,
USP11,
USP12,
USP13,
USP14,
USP15,
USP16,
USP17,
USP17L2,
USP17L3,
USP17L4,
USP17L5,
USP17L7,
USP17L8,
USP18,
USP19,
USP20,
USP21,
USP22
Ubiquitin specific peptidase 22 is a protein that in humans is encoded by the USP22 gene on chromosome 17
Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more ...
,
USP23,
USP24,
USP25,
USP26
USP26 is a peptidase enzyme. The USP26 gene is an X-linked gene exclusively expressed in the testis and it codes for the ubiquitin-specific protease 26. The USP26 gene is found at Xq26.2 on the X-chromosome as a single exon. The enzyme that this g ...
,
USP27X,
USP28,
USP29,
USP30,
USP31,
USP32,
USP33,
USP34,
USP35,
USP36,
USP37,
USP38,
USP39,
USP40,
USP41,
USP42
Ubiquitin carboxyl-terminal hydrolase 42 is an enzyme that in humans is encoded by the ''USP42'' gene.
References
Further reading
*
*
*
*
*
*
*
{{gene-7-stub ...
,
USP43,
USP44,
USP45,
USP46)
* the ovarian tumour (OTU) superfamily (
OTUB1,
OTUB2);
* and the Machado-Josephin domain (MJD) superfamily. (
ATXN3
Ataxin-3 is a protein that in humans is encoded by the ''ATXN3'' gene.
Clinical significance
Machado–Joseph disease, also known as spinocerebellar ataxia-3, is an autosomal dominant neurologic disorder. The protein encoded by the ''ATXN3'' g ...
,
ATXN3L)
* the ubiquitin C-terminal hydrolase (UCH) superfamily; (
BAP1
BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) is a deubiquitinating enzyme that in humans is encoded by the ''BAP1'' gene. ''BAP1'' encodes an 80.4 kDa nuclear-localizing protein with a ubiquitin carboxy-terminal hydrolase ( ...
,
UCHL1
Ubiquitin carboxy-terminal hydrolase L1 (, ''ubiquitin C-terminal hydrolase'', ''UCH-L1'') is a deubiquitinating enzyme.
Function
UCH-L1 is a member of a gene family whose products hydrolyze small C-terminal adducts of ubiquitin to generate ...
,
UCHL3
Ubiquitin carboxyl-terminal hydrolase isozyme L3 is an enzyme that in humans is encoded by the ''UCHL3'' gene.
Interactions
UCHL3 has been shown to interact with NEDD8 and the tauopathy and synucleinopathy associated mutated ubiquitin molecule UB ...
,
UCHL5)
*the MINDY family of K48-specific deubiquitinases; (
MINDY1,
MINDY2,
MINDY3,
MINDY4)
*the recently discovered ZUFSP family, at present solely represented by ZUP1
There is also a little known putative group of DUBs called the permutated papain fold peptidases of dsDNA viruses and eukaryote (PPPDEs) superfamily, which, if shown to be bona fide DUBs, would be the seventh in the cysteine protease class.
Metalloproteases
The Jab1/Mov34/Mpr1 Pad1 N-terminal+ (MPN+) (JAMM) domain superfamily proteins bind zinc and hence are metalloproteases.
Role of deubiquitinating enzymes

DUBs play several roles in the ubiquitin pathway. One of the best characterised functions of DUBs is the removal of
monoubiquitin and
polyubiquitin chains from proteins. These modifications are a
post translational modification
In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translate mRNA in ...
(addition to a protein after it has been made) where single ubiquitin proteins or chains of ubiquitin are added to lysines of a substrate protein. These ubiquitin modifications are added to proteins by the ubiquitination machinery;
ubiquitin-activating enzyme
Ubiquitin-activating enzymes, also known as E1 enzymes, catalyze the first step in the ubiquitination reaction, which (among other things) can target a protein for degradation via a proteasome. This covalent bond of ubiquitin or ubiquitin-like pro ...
s (E1s),
ubiquitin-conjugating enzyme
Ubiquitin-conjugating enzymes, also known as E2 enzymes and more rarely as ''ubiquitin-carrier enzymes'', perform the second step in the ubiquitination reaction that targets a protein for degradation via the proteasome. The ubiquitination process ...
s (E2s) and
ubiquitin ligase
A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin ...
s (E3s). The result is ubiquitin bound to lysine residues via an
isopeptide bond
An isopeptide bond is a type of amide bond formed between a carboxyl group of one amino acid and an amino group of another. An isopeptide bond is the linkage between the side chain amino or carboxyl group of one amino acid to the α-carboxyl, α- ...
.
Proteins are affected by these modifications in a number of ways: they regulate the degradation of proteins via the
proteasome
Proteasomes are essential protein complexes responsible for the degradation of proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are found inside all e ...
and
lysosome
A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...
; coordinate the
cellular localisation of proteins; activate and inactivate proteins; and modulate
protein-protein interactions.
DUBs play the antagonistic role in this axis by removing these modifications, therefore reversing the fate of the proteins.
In addition, a less understood role of DUBs is the cleavage of
ubiquitin-like protein
Ubiquitin-like proteins (UBLs) are a family of small proteins involved in post-translational modification of other proteins in a cell (biology), cell, usually with a regulatory protein, regulatory function. The UBL protein family derives its name ...
s such as
SUMO
is a form of competitive full-contact wrestling where a ''rikishi'' (wrestler) attempts to force his opponent out of a circular ring (''dohyō'') or into touching the ground with any body part other than the soles of his feet (usually by th ...
and
NEDD8
NEDD8 is a protein that in humans is encoded by the ''NEDD8'' gene. (in ''Saccharomyces cerevisiae'' this protein is known as Rub1) This ubiquitin-like protein, ubiquitin-like (UBL) protein becomes covalently conjugated to a limited number of cell ...
. Some DUBs may have the ability to cleave isopeptide bonds between these proteins and substrate proteins.
They activate ubiquitin by the
proteolysis
Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Protein degradation is a major regulatory mechanism of gene expression and contributes substantially to shaping mammalian proteomes. Uncatalysed, the hydrolysis o ...
(breaking down) of the inactive expressed forms of ubiquitin. Ubiquitin is encoded in mammals by 4 different genes:
UBA52
60S ribosomal protein L40 (RPL40) is a protein that in humans is encoded by the ''UBA52'' gene.
Function
Ubiquitin is a highly conserved nuclear and cytoplasmic protein that has a major role in targeting cellular proteins for degradation by ...
,
RPS27A
40S ribosomal protein S27a is a protein that in humans is encoded by the ''RPS27A'' gene.
Ubiquitin, a highly conserved protein that has a major role in targeting cellular proteins for degradation by the 26S proteosome, is synthesized as a prec ...
,
UBB and
UBC
The University of British Columbia (UBC) is a Public university, public research university with campuses near University of British Columbia Vancouver, Vancouver and University of British Columbia Okanagan, Kelowna, in British Columbia, Canada ...
. A similar set of genes is found in other eukaryotes such as yeast. The UBA52 and RPS27A genes produce ubiquitin that is fused to
ribosomal
Ribosomes () are macromolecular machines, found within all cells, that perform biological protein synthesis (messenger RNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA molecules to fo ...
proteins and the UBB and UBC genes produce polyubiquitin (a chain of ubiquitin joined by their
C- and
N-termini
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
).
DUBs cleave the ubiquitin from these proteins, producing active single units of ubiquitin.
DUBs also cleave single ubiquitin proteins that may have had their
C-terminal tails accidentally bound to small cellular
nucleophile
In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
s.
These ubiquitin-
amide
In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a chemical compound, compound with the general formula , where R, R', and R″ represent any group, typically organyl functional group, groups or hydrogen at ...
s and ubiquitin-
thioester
In organic chemistry, thioesters are organosulfur compounds with the molecular structure . They are analogous to carboxylate esters () with the sulfur in the thioester replacing oxygen in the carboxylate ester, as implied by the thio- prefix ...
s may be formed during standard ubiquitination reactions by the E1-E2-E3 cascade.
Glutathione
Glutathione (GSH, ) is an organic compound with the chemical formula . It is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources ...
and
polyamine
A polyamine is an organic compound having two or more amino groups. Alkyl polyamines occur naturally, but some are synthetic. Alkylpolyamines are colorless, hygroscopic, and water soluble. Near neutral pH, they exist as the ammonium derivatives. ...
s are two nucleophiles that might attack the thioester bond between ubiquitin and these enzymes. Ubiquitin C-terminal hydrolase is an example of the DUB that hydrolyses these bonds with broad specificity.
Free polyubiquitin chains are cleaved by DUBs to produce monoubiquitin. The chains may be produced by the E1-E2-E3 machinery in the cell free from any substrate protein. Another source of free polyubiquitin is the product of ubiquitin-substrate cleavage. If DUBs cleave the base of the polyubiquitin chain that is attached to a protein, the whole chain will become free and needs to be recycled by DUBs.
Domains

DUBs often contain a
catalytic
Catalysis () is the increase in reaction rate, rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst ...
domain
A domain is a geographic area controlled by a single person or organization. Domain may also refer to:
Law and human geography
* Demesne, in English common law and other Medieval European contexts, lands directly managed by their holder rather ...
surrounded by one or more accessory domains, some of which contribute to target recognition. These additional domains include domain present in ubiquitin-specific proteases (DUSP) domain; ubiquitin-like (UBL) domain; meprin and TRAF homology (MATH) domain; zinc-finger ubiquitin-specific protease (ZnF-UBP) domain; zinc-finger myeloid, nervy and DEAF1 (ZnF-MYND) domain; ubiquitin-associated (UBA) domain; CHORD-SGT1 (CS) domain; microtubule-interacting and trafficking (MIT) domain; rhodanese-like domain; TBC/RABGAP domain; and B-box domain.
Catalytic domain
The catalytic domain of DUBs is what classifies them into particular groups; USPs, OTUs, MJDs, UCHs and MPN+/JAMMs. The first 4 groups are
cysteine protease
Cysteine proteases, also known as thiol proteases, are hydrolase enzymes that degrade proteins. These proteases share a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic triad or dyad.
Discovered by Gopal Chu ...
s, whereas the latter is a zinc
metalloprotease
A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myoge ...
. The cysteine protease DUBs are
papain-like and thus have a similar mechanism of action. They use either catalytic dyads or
triads (either two or three
amino acids
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...
) to catalyse the
hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
of the
amide bond
In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent any group, typically organyl groups or hydrogen atoms. The amide group is called a p ...
s between ubiquitin and the substrate. The active site residues that contribute to the catalytic activity of the cysteine protease DUBs are
cysteine
Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...
(dyad/triad),
histidine
Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...
(dyad/triad) and
aspartate
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protein ...
or
asparagine
Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...
(triad only). The histidine is polarised by the aspartate or asparagine in catalytic triads or by other ways in dyads. This polarised residue lowers the pKa of the cysteine, allowing it to perform a
nucleophilic attack
In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they a ...
on the
isopeptide bond
An isopeptide bond is a type of amide bond formed between a carboxyl group of one amino acid and an amino group of another. An isopeptide bond is the linkage between the side chain amino or carboxyl group of one amino acid to the α-carboxyl, α- ...
between the ubiquitin
C-terminus
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein
Proteins are large biomolecules and macromolecules that comp ...
and the substrate
lysine
Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. Lysine contains an α-amino group (which is in the protonated form when the lysine is dissolved in water at physiological pH), an α-carboxylic acid group ( ...
. Metalloproteases coordinate
zinc
Zinc is a chemical element; it has symbol Zn and atomic number 30. It is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic tabl ...
ions with histidine, aspartate and
serine
Serine
(symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...
residues, which activate water molecules and allows them to attack the isopeptide bond.
UBL
Ubiquitin-like (UBL) domains have a similar structure (fold) to ubiquitin, except they lack the terminal glycine residues. 18 USPs are proposed to have UBL domains. Only 2 other DUBs have UBLs outside the USP group:
OTU1 and
VCPIP1. USP4, USP7, USP11, USP15, USP32, USP40 and USP47 have multiple UBL domains. Sometimes the UBL domains are in tandem, such as in USP7 where 5 tandem
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...
UBL domains are present. USP4, USP6, USP11, USP15, USP19, USP31, USP32 and USP43 have UBL domains inserted into the catalytic domain. The functions of UBL domains are different between USPs, but commonly they regulate USP catalytic activity. They can coordinate localisation at the proteasome (USP14); negatively regulate USPs by competing for the catalytic site of the USP (USP4), and induce conformational changes to increase catalytic activity (USP7).
Like other UBL domains, the structure of USP UBL domains show a β-grasp fold.
DUSP
Single or multiple tandem DUSP domains of approximately 120 residues are found in six USPs. The function of the DUSP domain is currently unknown but it may play a role in
protein-protein interaction, in particular to DUBs substrate recognition. This is predicted because of the hydrophobic cleft present in the DUSP domain of USP15 and that some protein interactions with DUSP containing USPs do not occur without these domains. The DUSP domain displays a novel tripod-like
fold comprising three
helices
A helix (; ) is a shape like a cylindrical coil spring or the thread of a machine screw. It is a type of smoothness (mathematics), smooth space curve with tangent lines at a constant angle to a fixed axis. Helices are important in biology, as ...
and an anti-parallel
beta-sheet
The beta sheet (β-sheet, also β-pleated sheet) is a common structural motif, motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone chain, backbon ...
made of three strands. This fold resembles the legs (helices) and seat (beta-sheet) of the tripod. Within most DUSP domains in USPs there is a
conserved sequence of amino acids known as the PGPI
motif. This is a sequence of four amino acids;
proline
Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...
,
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...
, proline and
isoleucine
Isoleucine (symbol Ile or I) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...
, which packs against the three-helix bundle and is highly ordered.
Role in disease
The full extent of the role of DUBs in diseases remains to be elucidated. Their involvement in disease is predicted due to known roles in physiological processes that are involved in disease states; including cancer and neurological disorders.
The enzyme USP28 is over-expressed in different types of
cancer
Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
such as colon or lung. In addition,
USP28 deubiquitinates and stabilizes important oncogenes such as
c-Myc
''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' ( MYC), ''l-myc'' ( MYCL), and ''n-myc'' ( MYCN). ''c-myc'' (also sometimes ...
,
Notch1
Neurogenic locus notch homolog protein 1 (Notch 1) is a protein encoded in humans by the ''NOTCH1'' gene. Notch 1 is a single-pass transmembrane receptor.
Function
This gene encodes a member of the Notch family. Members of this type 1 transm ...
,
c-jun
Transcription factor Jun is a protein that in humans is encoded by the ''JUN'' gene. c-Jun, in combination with protein c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only l ...
or
ΔNp63.
In squamous tumors, USP28 regulates the resistance to chemotherapy regulating DNA repair via
ΔNp63-Fanconia anemia pathway axis.
The deubiquitinating enzymes UCH-L3 and YUH1 are able to hydrolyse mutant ubiquitin
UBB+1 UBB or Ubb may refer to:
Education
* Babeș-Bolyai University in Cluj-Napoca, Romania
* University of Bangka Belitung in Pangkalpinang, Indonesia
* University of Bío Bío in Chile
Media
* ''Ultimate Big Brother'', British reality television sho ...
despite the fact that the glycine at position 76 is mutated.
UCH-L1 levels are high in various types of malignancies (
cancer
Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
).
Role in the cell cycle
DUBs play an active role in modulating the cell cycle. Ubiquitin-specific-processing protease (USP) is a family of deubiquitinating enzymes that play a crucial role in cell cycle regulation.
Two such enzymes include USP17 and USP44. USP17 regulates pathways responsible for progressing cells through the cell cycle.
Its targets include regulators of Ras, CDK2, and Cyclin A.
USP44 plays an important role in anaphase initiation.
New research into the mitotic checkpoint has revealed a novel role for USP44 in regulating cell cycle progression.
USP regulation of Ras
The ERK Pathway allows for the transduction of external mitogenic signals into intracellular signals promoting cellular proliferation. One of the key regulators of this pathways is Ras, a GTPase that, upon activation, binds GTP to "turn on" the subsequent signaling cascade. Ras converting enzyme 1 (RCE1) post-translationally cleaves the 3 residues on the C-terminus of Ras, allowing Ras to properly localize to the plasma membrane.
USP17 acts to deubiquitinate K63-ubiquitin domains on RCE1.
Such stabilization of RCE1 allows for proper localization of Ras, thus promoting proliferation upon activation of early receptors in the ERK Pathway. Ras hyperactivity can result in cell cycle dysregulation.
Thus, regulation of Ras through USP17 acts as another point in Ras regulation.
USP regulation of G1-S transition
Cyclin-dependent kinases (CDKs) are a family of enzymes that phosphorylate serine and threonine residues to drive the cell through the cell cycle. Activation of CDK2 is critical for the G1-S transition. For CDK2 to be activated, cyclin A must bind to the cyclin-dependent kinase complex (CDKC). Cell division cycle 25A (CDC25A) is a phosphatase that removes an inhibitory phosphate group from CDK2.
While ubiquitination would mark CDC25A for degradation, thus blocking progression to S phase, USP17 deubiquitinates CDC25A.
An increase in CDC25A stability promotes CDKC activity, thus driving the cell through the G1-S transition.
USP17 also regulates cell cycle progression by acting on SETD8 to downregulate transcription of cyclin-dependent kinase inhibitor 1 (CDKN1A), also known as p21.
CDKN1A binds to and inhibits CDK2 using its N-terminal binding domain, thus blocking progression through the G1-S transition. SETD8, a methyltransferase, uses S-Adenosyl methionine to methylate the Lys20 residue of histone 4, resulting in the condensation of chromosomes.
This compaction of the DNA downregulates CDKN1A transcription. USP17 deubiquitinates SETD8, thus reducing its propensity for degradation and increasing its intracellular stability.
The resulting downregulation in CDKN1A transcription promotes CDK2 activity, allowing the cell to progress through the G1-S transition. See schematic of the role of DUBs in the cell cycle regulation.
USP44 in anaphase initiation
The spindle checkpoint (also referred to as the mitotic checkpoint) ensures proper separation of chromosomes. Broadly, the mitotic checkpoint promotes fidelity in chromosomal segregation, increasing the likelihood that each daughter cell receives only one duplicated chromosome.
Such a mechanism is crucial, as errors in chromosomal separation have been implicated in cancer, birth defects, and antibiotic resistance in pathogens.
One of the core regulator proteins is the anaphase-promoting complex (APC/C). APC/C ubiquitinates securin.
The resulting destruction of securing release separase,
which hydrolyzes cohesion – the protein that binds sister chromatids together.
New research from Stegmeier and colleagues
published in the journal Nature demonstrates a crucial role for USP44 in regulating the spindle checkpoint. Using an shRNA screen, USP44 was identified to stabilize the inhibition of APC/C
The binding of CDC20 to APC/C is required for the ubiquitination of securin.
A protein called hMAD2 can form an inactive trimer with APC and CDC20, forming the hMAD2-CDC-APC complex.
Upon the ubiquitination of CDC20 by UbcH10, hMAD2 dissociates, and APC/C becomes active.
It is important to note that ubiquitination of CDC20 does not serve to mark it for degradation, but rather promote dissociation of hMAD2 from the hMAD2-CDC-APC complex. USP44, a ubiquitin-specific-processing protease, can stabilize the inactive hMAD2-CDC-APC complex by counteracting UbcH10 ubiquitination. This blocks hMAD2 dissociation and allows for proper regulation of APC/C, keeping it inactive until proper attachment of the mitotic spindle. Upon proper attachment, switch-like behavior allows for the activation of APC/C.
This results in the cleavage of cohesion, allowing for the separation of sister chromatids.
Role in p53-mediated DNA damage repair
DNA damage can prove catastrophic for an organism. Mechanisms for DNA mutation include oxidative stress, DNA replication errors, exogenous carcinogens, radiation, and spontaneous base mutation. Upon DNA damage, cell cycle progression is halted to prevent propagation of the mutation. The TP53 gene (also known as p53) is crucial in ensuring the conservation of the genome.
Deubiquitinating enzymes play an integral role in maintaining p53's function.
In healthy cells, p53 activates the E3 ubiquitin ligase MDM2 which in turn ubiquitinates p53. This creates a
negative feedback
Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused ...
loop, whereby the degradation of p53 allows for cells to flow through the cell cycle. Upon DNA damage, Ubiquitin-specific-processing protease 7 (USP7) stabilizes p53 by cleaving ubiquitin.
For USP7 to deubiquitinate p53, it must localize to the nucleus. However, no nuclear localization sequence (NLS) has been found.
Despite no known NLS, one study showed that, upon deletion of USP7's N-terminus, no nuclear localization occurred.
It is possible that other proteins facilitate nuclear entry of USP7.
Once stabilized, p53 can exert its tumor suppression function. Downstream pathways of p53 act to either halt cell cycle progression in G1 or G2 phases of the cell cycle
or promote cell-death, depending on the severity of the DNA damage.
See schematic of the role of USP7 in the p53-dependent pathway.
or promote cell-death, depending on the severity of the DNA damage.
See schematic of the role of USP7 in the p53-dependent pathway.
References
{{InterPro content, IPR006615
Protein domains
Enzymes