USP1 (ubiquitin specific peptidase 1)

2013-10-01   Iraia García-Santisteban , Godefridus J Peters , Jose A Rodriguez , Elisa Giovannetti 





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.


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).


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.


No reported pseudogenes. Paralogs for USP1 gene include USP12, USP35, USP38, and USP46.


Atlas Image
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.


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.


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 subjected to proteasomal degradation (Huang et al., 2006; Piatkov et al., 2012).


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).


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).


The USP1 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, and mosquito.



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. Most of the modifications are missense mutations whose functional consequences need to be addressed.
Atlas Image
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.

Implicated in

Entity name
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.
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).
Entity name
Lung cancer
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).
Entity name
Fanconi anemia (FA)
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 DAndrea, 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. 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).


Pubmed IDLast YearTitleAuthors
180826042007A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway.Cohn MA et al
221012652011Insights into phosphorylation-dependent mechanisms regulating USP1 protein stability during the cell cycle.Cotto-Rios XM et al
98068421998Identification and chromosomal assignment of USP1, a novel gene encoding a human ubiquitin-specific protease.Fujiwara T et al
239379062013USP1 deubiquitinase: cellular functions, regulatory mechanisms and emerging potential as target in cancer therapy.García-Santisteban I et al
165319952006Regulation of monoubiquitinated PCNA by DUB autocleavage.Huang TT et al
231146022012Molecular pathogenesis and clinical management of Fanconi anemia.Kee Y et al
192174322009Inactivation of murine Usp1 results in genomic instability and a Fanconi anemia phenotype.Kim JM et al
232847582012Integrative proteomics and tissue microarray profiling indicate the association between overexpressed serum proteins and non-small cell lung cancer.Liu Y et al
156943352005The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway.Nijman SM et al
126456532003Chromosomal alterations in osteosarcoma cell lines revealed by comparative genomic hybridization and multicolor karyotyping.Ozaki T et al
205063032010Hematopoietic stem cell defects in mice with deficiency of Fancd2 or Usp1.Parmar K et al
231597362012The auto-generated fragment of the Usp1 deubiquitylase is a physiological substrate of the N-end rule pathway.Piatkov KI et al
216859362012Regulation of the activation of the Fanconi anemia pathway by the p21 cyclin-dependent kinase inhibitor.Rego MA et al
174606942007FANCI is a second monoubiquitinated member of the Fanconi anemia pathway.Sims AE et al
108620392000Chromosomal regions involved in the pathogenesis of osteosarcomas.Stock C et al
231161192012Serine phosphorylation is critical for the activation of ubiquitin-specific protease 1 and its interaction with WD40-repeat protein UAF1.Villamil MA et al
219253152011USP1 deubiquitinates ID proteins to preserve a mesenchymal stem cell program in osteosarcoma.Williams SA et al
224269992012USP1 regulates AKT phosphorylation by modulating the stability of PHLPP1 in lung cancer cells.Zhiqiang Z et al

Other Information

Locus ID:

NCBI: 7398
MIM: 603478
HGNC: 12607
Ensembl: ENSG00000162607


dbSNP: 7398
ClinVar: 7398
TCGA: ENSG00000162607


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Fanconi anemia pathwayKEGGko03460
Fanconi anemia pathwayKEGGhsa03460
DNA Damage BypassREACTOMER-HSA-73893
Recognition of DNA damage by PCNA-containing replication complexREACTOMER-HSA-110314
Fanconi Anemia PathwayREACTOMER-HSA-6783310

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
156943352005The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway.221
219253152011USP1 deubiquitinates ID proteins to preserve a mesenchymal stem cell program in osteosarcoma.81
217682872011APC/CCdh1-dependent proteolysis of USP1 regulates the response to UV-mediated DNA damage.37
216401072011Dynamic regulation of PCNA ubiquitylation/deubiquitylation.21
213890832011USP1 deubiquitinase maintains phosphorylated CHK1 by limiting its DDB1-dependent degradation.19
260328342016USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance.18
231161192012Serine phosphorylation is critical for the activation of ubiquitin-specific protease 1 and its interaction with WD40-repeat protein UAF1.15
195366492009The Fanconi anemia family of genes and its correlation with breast cancer susceptibility and breast cancer features.13
224269992012USP1 regulates AKT phosphorylation by modulating the stability of PHLPP1 in lung cancer cells.12
269519302016PDGF Engages an E2F-USP1 Signaling Pathway to Support ID2-Mediated Survival of Proneural Glioma Cells.12


Iraia García-Santisteban ; Godefridus J Peters ; Jose A Rodriguez ; Elisa Giovannetti

USP1 (ubiquitin specific peptidase 1)

Atlas Genet Cytogenet Oncol Haematol. 2013-10-01

Online version: