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Gene Section
Review
USP1 (ubiquitin specific peptidase 1)
Iraia García-Santisteban, Godefridus J Peters, Jose A Rodriguez, Elisa Giovannetti
Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque
Country UPV/EHU, Leioa, Spain (IGS, JAR), Department of Medical Oncology, VU University
Medical Center, Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands (GJP, EG)
Published in Atlas Database: October 2013
Online updated version : http://AtlasGeneticsOncology.org/Genes/USP1ID43072ch1p31.html
DOI: 10.4267/2042/53649
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
Description
Review on USP1, with data on DNA/RNA, on the
protein encoded and where the gene is implicated.
Ubiquitin specific peptidase 1 is located at
chromosome 1 in the region p31.3. USP1 was first
cloned in 1998 as part of the Human Genome
Project (Fujiwara et al., 1998).
Identity
Transcription
Other names: UBP
HGNC (Hugo): USP1
Location: 1p31.3
Local order: Based on Mapviewer, genes flanking
USP1 are:
- L1TD1 (LINE-1 type transposase domain
containing 1); 1p31.3
- ANKRD38 (ankyrin repeat domain 38); 1p31.3
- USP1 (ubiquitin specific peptidase 1); 1p31.3
- DOCK7 (dedicator of cytokinesis 7); 1p31.3
- ANGPTL3 (angiopoietin-like 3); 1p31.1-p22.3.
USP1 transcription is controlled by different
mechanisms. On one hand, USP1 mRNA levels
fluctuate during the cell cycle, reaching a peak in S
phase, and remaining low before and after it
(Nijman et al., 2005).
On the other hand, DNA damaging agents can
repress USP1 transcription by a mechanism that
involves p21 cyclin dependent kinase inhibitor
(Rego et al., 2012).
Transcription produces 10 different mRNAs, 6
alternatively spliced variants and 4 unspliced forms.
There are 5 probable alternative promotors, 2 non
overlapping alternative last exons and 9 validated
alternative polyadenylation sites.
The mRNAs appear to differ by truncation of the 5'
end, overlapping exons with different boundaries.
Efficacy of translation may be reduced by the
presence of a shorter translated product (uORF)
initiating at an AUG upstream of the main open
reading frame.
DNA/RNA
Note
Structural organization of USP1 gene: USP1
gene is located on chromosome 1. 3 transcripts of
this gene, encoding the same protein product, have
been identified.
The gene contains 14 distinct gt-ag introns.
Structural organization of USP1 protein. Cys and His boxes containing the catalytic residues (C90, H593, D751) are
represented in green. The "degradation signal" (Degron) that mediates APC/CCdh1-mediated degradation of USP1 is shown in
orange, also the location of the Serine 313 CDK phosphorylation site is highlighted. The diglycine motif (Gly-Gly) represented in
purple constitutes the USP1 autocleavage site. Nuclear localization signals (NLSs) are illustrated in blue.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5)
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USP1 (ubiquitin specific peptidase 1)
García-Santisteban I, et al.
subjected to proteasomal degradation (Huang et al.,
2006; Piatkov et al., 2012).
Pseudogene
No reported pseudogenes. Paralogs for USP1 gene
include USP12, USP35, USP38, and USP46.
Localisation
The localization of USP1 is nuclear. USP1 bears
two nuclear localization signals (NLSs) which
mediate the import of the USP1/UAF1 complex to
the cell nucleus, where it exerts its function
(García-Santisteban et al., 2012b). USP1 also
contains a nuclear export signal (NES, not indicated
in the figure) that was shown to be functional in an
export assay, but whose function in the context of
the full length protein needs to be evaluated
(García-Santisteban et al., 2012a).
Protein
Description
USP1 gene encodes a 785 amino acid protein with a
predicted molecular weight of 88,2 kDa (Fujiwara
et al., 1998). USP1 belongs to the ubiquitin specific
protease (USP) family of human deubiquitinases
(DUBs). Like other members of its family, it
harbours a highly conserved USP domain
organization comprising a N-terminal Cys box and
a C-terminal His box, which contain the catalytic
residues (C90, H593 and D751) (Fujiwara et al.,
1998; Villamil et al., 2012a; Békés et al., 2013).
The enzymatic activity of USP1 alone is relatively
low, but is enhanced upon binding to USP1
associated factor 1 (UAF1) (Cohn et al., 2007;
Villamil et al., 2012a). The UAF1 binding region in
USP1 is somewhat controversial, since two binding
motifs have been proposed based on different
experimental approaches. Villamil and co-workers
proposed that the UAF1 binding region comprised
residues 235-408 (Villamil et al., 2012b), but
García-Santisteban et al. described that the binding
motif was between amino acid residues 420-520
(García-Santisteban et al., 2012a). Further
experimental evidence should clarify this
controversy.
Function
USP1, together with UAF1, plays an important role
in the DNA damage response, mainly in the
Fanconi anemia (FA) pathway and in the process of
translesion synthesis (TLS). Deubiquitination of
FANCD2 and FANCI by the USP1/UAF1 complex
is an essential step for the correct function of the
FA pathway (Nijman et al., 2005; Sims et al.,
2007). In addition, the USP1/UAF1 complex
mediates the deubiqutination of Proliferating Cell
Nuclear Antigen (PCNA), preventing the
recruitment of low fidelity DNA polymerases in the
absence of DNA damage (Huang et al., 2006).
In addition to its DNA damage-related functions,
USP1 has also been reported to deubiquitinate and
stabilize three members of the family of inhibitors
of DNA binding (ID) proteins (ID1, ID2 and ID3),
and
thus
contributing
to
preserve
the
undifferentiated state of osteosarcoma cells
(Williams et al., 2011).
Expression
USP1 protein levels can be regulated through
different mechanisms that involve proteasome
mediated degradation. On one hand, anaphase
promoting complex/cyclosomeCdh1 (APC/CCdh1)
recognizes the 295-342 amino acid region (Degron)
in USP1, mediating its degradation by the
proteasome (Cotto-Rios et al., 2011a). The serine
313 residue located in this region is phosphorylated
by cyclin dependent kinases (CDKs), which might
prevent USP1 degradation in mitosis (Cotto-Rios et
al., 2011b). On the other hand, UV damage causes
USP1 autocleavage at an internal diglycine motif
(Gly-Gly) located in the C-terminal end of the
protein. The resulting USP1 fragments are
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5)
Homology
The USP1 gene is conserved in chimpanzee,
Rhesus monkey, dog, cow, mouse, rat, chicken,
zebrafish, fruit fly, and mosquito.
Mutations
Note
A survey in the COSMIC mutation database
(accession date: 16 September 2013) revealed a
total of 40 mutations that lead to different
modifications in different human tumors.
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USP1 (ubiquitin specific peptidase 1)
García-Santisteban I, et al.
Cancer-associated mutations in USP1. Schematic representation of USP1 protein showing the position of cancer-associated
USP1 mutations reported to date (September 2013) in the COSMIC mutation database. Missense amino acid substitutions are
indicated in black, nonsense amino acid substitutions in red and frameshift insertion/deletions in blue. Synonymous amino acid
substitutions have been omitted. The Table shows the detailed list of mutations, including the DNA modification (CDS Mutation),
protein modification (AA Mutation), type of mutation and tissue.
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Most of the modifications are missense mutations
whose functional consequences need to be
addressed.
Disruption of the USP1 gene in mice results in
genomic instability and FA phenotype, and also
leads to defects in hematopoietic stem cell
maintenance (Kim et al., 2009; Parmar et al., 2010).
Implicated in
To be noted
Osteosarcoma
Note
A recent study showed that USP1 mRNA and
protein levels were elevated in a subset of primary
osteosarcoma tumors, and that increased USP1
levels correlated with increased levels of its
substrate ID2. This observation is consistent with
the finding that USP1 deubiquitinates and stabilizes
ID proteins, contributing to preserve the
undifferentiated state of osteosarcoma cells.
Cytogenetics
Comparative genomic hybridization (CGH)
analyses found that the USP1 locus 1p31.3 was
amplified in 26%-57% of osteosarcoma tumors
(Ozaki et al., 2003; Stock et al., 2000).
Note
This work was supported by the Basque Country
Government Department of Industry (grant number
ETORTEK BioGUNE2010 to JAR), the Spanish
Government MICINN (Ministerio de Ciencia e
Innovacion) (grant number BFU2009-13245 to
JAR), the University of the Basque Country
(UFI11/20), Department of Education of the
Basque Country Government Fellowship (to IG-S),
the Netherlands Organization for Scientific
Research, Veni grant (to EG) and CCA Foundation
(grant number 2012-5-07 to EG and GJP).
Lung cancer
Fujiwara T, Saito A, Suzuki M, Shinomiya H, Suzuki T,
Takahashi E, Tanigami A, Ichiyama A, Chung CH,
Nakamura Y, Tanaka K. Identification and chromosomal
assignment of USP1, a novel gene encoding a human
ubiquitin-specific protease. Genomics. 1998 Nov
15;54(1):155-8
References
Note
One study reported lower USP1 mRNA and protein
levels in lung cancer cells and tissues (Zhiqiang et
al., 2012). However, most data support the view
that USP1 is overexpressed in lung cancer. Thus, a
survey in the Oncomine research edition database
revealed that USP1 was overexpressed in 25% of
the lung cancer microarray datasets available, while
none of these studies reported significant
downregulation of USP1 (García-Santisteban et al.,
2013).
In
line
with
these
data,
immunohistochemical analysis on a NSCLC tissue
microarray revealed USP1 overexpression (Liu et
al., 2012). An association between USP1
overexpression with lung cancer was already
demonstrated in a recent study on USP1 mRNA
expression in NSCLC tissue and cell lines
indicating that USP1 expression was higher in
tumors and tumor-derived cells than in normal lung
tissue (García-Santisteban et al., 2013).
Stock C, Kager L, Fink FM, Gadner H, Ambros PF.
Chromosomal regions involved in the pathogenesis of
osteosarcomas. Genes Chromosomes Cancer. 2000
Jul;28(3):329-36
Ozaki T, Neumann T, Wai D, Schäfer KL, van Valen F,
Lindner N, Scheel C, Böcker W, Winkelmann W,
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Chromosomal alterations in osteosarcoma cell lines
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Nijman SM, Huang TT, Dirac AM, Brummelkamp TR,
Kerkhoven RM, D'Andrea AD, Bernards R. The
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Huang TT, Nijman SM, Mirchandani KD, Galardy PJ, Cohn
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Fanconi anemia (FA)
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D'Andrea AD. A UAF1-containing multisubunit protein
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Note
Fanconi anemia (FA) is a rare hereditary disorder
that results in congenital abnormalities, progressive
bone
marrow
failure,
DNA
crosslinker
hypersensitivity, genomic instability and increased
susceptibility to cancer (Kee and D'Andrea, 2012).
The disorder is the result of mutations in any of at
least 15 genes that regulate the DNA repair
pathway that corrects interstrand crosslinks (ICLs).
USP1 cannot be considered a bona fide FA gene,
since mutations in USP1 have not been identified in
FA patients yet. However, recent evicence supports
the view that USP1 is crucial for the correct
regulation of the FA pathway.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5)
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Kutok JL, D'Andrea AD. Inactivation of murine Usp1
results in genomic instability and a Fanconi anemia
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Parmar K, Kim J, Sykes SM, Shimamura A, Stuckert P,
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This article should be referenced as such:
García-Santisteban I, Peters GJ, Rodriguez JA,
Giovannetti E. USP1 (ubiquitin specific peptidase 1). Atlas
Genet Cytogenet Oncol Haematol. 2014; 18(5):351-355.
Piatkov KI, Colnaghi L, Békés M, Varshavsky A, Huang
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5)
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