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USP1 (ubiquitin specific peptidase 1)

Written2013-10Iraia García-Santisteban, Godefridus J Peters, Jose A Rodriguez, Elisa Giovannetti
Department of Genetics, Physical Anthropology, 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)

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HGNC (Hugo) USP1
HGNC Previous nameubiquitin specific protease 1
LocusID (NCBI) 7398
Atlas_Id 43072
Location 1p31.3  [Link to chromosome band 1p31]
Location_base_pair Starts at 62437049 and ends at 62451804 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping USP1.png]
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.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
USP1 (1p31.3)::ADAM9 (8p11.22)USP1 (1p31.3)::EFCAB7 (1p31.3)USP1 (1p31.3)::SGIP1 (1p31.3)
USP1 (1p31.3)::USP1 (1p31.3)


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.
Description 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).
Transcription 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.
Pseudogene No reported pseudogenes. Paralogs for USP1 gene include USP12, USP35, USP38, and USP46.


  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.
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.
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 subjected to proteasomal degradation (Huang et al., 2006; Piatkov et al., 2012).
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).
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).
Homology The USP1 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, and mosquito.


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. Most of the modifications are missense mutations whose functional consequences need to be addressed.
  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 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).
Entity Lung cancer
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).
Entity Fanconi anemia (FA)
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. 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).

To be noted

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).


Ubiquitin-specific peptidase 1.
Bekes M, Huang T.
Handbook of proteolytic enzymes. Volume 1. 3rd edition. Edited by Rawlings ND, Salvesen G.; 2013: 2079-2085.
A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway.
Cohn MA, Kowal P, Yang K, Haas W, Huang TT, Gygi SP, D'Andrea AD.
Mol Cell. 2007 Dec 14;28(5):786-97.
PMID 18082604
Insights into phosphorylation-dependent mechanisms regulating USP1 protein stability during the cell cycle.
Cotto-Rios XM, Jones MJ, Huang TT.
Cell Cycle. 2011b Dec 1;10(23):4009-16. doi: 10.4161/cc.10.23.18501. Epub 2011 Dec 1. (REVIEW)
PMID 22101265
Identification and chromosomal assignment of USP1, a novel gene encoding a human ubiquitin-specific protease.
Fujiwara T, Saito A, Suzuki M, Shinomiya H, Suzuki T, Takahashi E, Tanigami A, Ichiyama A, Chung CH, Nakamura Y, Tanaka K.
Genomics. 1998 Nov 15;54(1):155-8.
PMID 9806842
USP1 deubiquitinase: cellular functions, regulatory mechanisms and emerging potential as target in cancer therapy.
Garcia-Santisteban I, Peters GJ, Giovannetti E, Rodriguez JA.
Mol Cancer. 2013 Aug 10;12:91. doi: 10.1186/1476-4598-12-91. (REVIEW)
PMID 23937906
Regulation of monoubiquitinated PCNA by DUB autocleavage.
Huang TT, Nijman SM, Mirchandani KD, Galardy PJ, Cohn MA, Haas W, Gygi SP, Ploegh HL, Bernards R, D'Andrea AD.
Nat Cell Biol. 2006 Apr;8(4):339-47. Epub 2006 Mar 12.
PMID 16531995
Molecular pathogenesis and clinical management of Fanconi anemia.
Kee Y, D'Andrea AD.
J Clin Invest. 2012 Nov 1;122(11):3799-806. doi: 10.1172/JCI58321. Epub 2012 Nov 1. (REVIEW)
PMID 23114602
Inactivation of murine Usp1 results in genomic instability and a Fanconi anemia phenotype.
Kim JM, Parmar K, Huang M, Weinstock DM, Ruit CA, Kutok JL, D'Andrea AD.
Dev Cell. 2009 Feb;16(2):314-20. doi: 10.1016/j.devcel.2009.01.001.
PMID 19217432
Integrative proteomics and tissue microarray profiling indicate the association between overexpressed serum proteins and non-small cell lung cancer.
Liu Y, Luo X, Hu H, Wang R, Sun Y, Zeng R, Chen H.
PLoS One. 2012;7(12):e51748. doi: 10.1371/journal.pone.0051748. Epub 2012 Dec 19.
PMID 23284758
The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway.
Nijman SM, Huang TT, Dirac AM, Brummelkamp TR, Kerkhoven RM, D'Andrea AD, Bernards R.
Mol Cell. 2005 Feb 4;17(3):331-9.
PMID 15694335
Chromosomal alterations in osteosarcoma cell lines revealed by comparative genomic hybridization and multicolor karyotyping.
Ozaki T, Neumann T, Wai D, Schafer KL, van Valen F, Lindner N, Scheel C, Bocker W, Winkelmann W, Dockhorn-Dworniczak B, Horst J, Poremba C.
Cancer Genet Cytogenet. 2003 Jan 15;140(2):145-52.
PMID 12645653
Hematopoietic stem cell defects in mice with deficiency of Fancd2 or Usp1.
Parmar K, Kim J, Sykes SM, Shimamura A, Stuckert P, Zhu K, Hamilton A, Deloach MK, Kutok JL, Akashi K, Gilliland DG, D'andrea A.
Stem Cells. 2010 Jul;28(7):1186-95. doi: 10.1002/stem.437.
PMID 20506303
The auto-generated fragment of the Usp1 deubiquitylase is a physiological substrate of the N-end rule pathway.
Piatkov KI, Colnaghi L, Bekes M, Varshavsky A, Huang TT.
Mol Cell. 2012 Dec 28;48(6):926-33. doi: 10.1016/j.molcel.2012.10.012. Epub 2012 Nov 15.
PMID 23159736
Regulation of the activation of the Fanconi anemia pathway by the p21 cyclin-dependent kinase inhibitor.
Rego MA, Harney JA, Mauro M, Shen M, Howlett NG.
Oncogene. 2012 Jan 19;31(3):366-75. doi: 10.1038/onc.2011.237. Epub 2011 Jun 20.
PMID 21685936
FANCI is a second monoubiquitinated member of the Fanconi anemia pathway.
Sims AE, Spiteri E, Sims RJ 3rd, Arita AG, Lach FP, Landers T, Wurm M, Freund M, Neveling K, Hanenberg H, Auerbach AD, Huang TT.
Nat Struct Mol Biol. 2007 Jun;14(6):564-7. Epub 2007 Apr 25.
PMID 17460694
Chromosomal regions involved in the pathogenesis of osteosarcomas.
Stock C, Kager L, Fink FM, Gadner H, Ambros PF.
Genes Chromosomes Cancer. 2000 Jul;28(3):329-36.
PMID 10862039
Serine phosphorylation is critical for the activation of ubiquitin-specific protease 1 and its interaction with WD40-repeat protein UAF1.
Villamil MA, Liang Q, Chen J, Choi YS, Hou S, Lee KH, Zhuang Z.
Biochemistry. 2012b Nov 13;51(45):9112-23. doi: 10.1021/bi300845s. Epub 2012 Nov 1.
PMID 23116119
USP1 deubiquitinates ID proteins to preserve a mesenchymal stem cell program in osteosarcoma.
Williams SA, Maecker HL, French DM, Liu J, Gregg A, Silverstein LB, Cao TC, Carano RA, Dixit VM.
Cell. 2011 Sep 16;146(6):918-30. doi: 10.1016/j.cell.2011.07.040.
PMID 21925315
USP1 regulates AKT phosphorylation by modulating the stability of PHLPP1 in lung cancer cells.
Zhiqiang Z, Qinghui Y, Yongqiang Z, Jian Z, Xin Z, Haiying M, Yuepeng G.
J Cancer Res Clin Oncol. 2012 Jul;138(7):1231-8. doi: 10.1007/s00432-012-1193-3. Epub 2012 Mar 20.
PMID 22426999


This paper should be referenced as such :
Garc_a-Santisteban, I ; Peters, GJ ; Rodriguez, JA ; Giovannetti, E
USP1 (ubiquitin specific peptidase 1)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(5):351-355.
Free journal version : [ pdf ]   [ DOI ]

External links


HGNC (Hugo)USP1   12607
Atlas Explorer : (Salamanque)USP1
Entrez_Gene (NCBI)USP1    ubiquitin specific peptidase 1
GeneCards (Weizmann)USP1
Ensembl hg19 (Hinxton)ENSG00000162607 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000162607 [Gene_View]  ENSG00000162607 [Sequence]  chr1:62437049-62451804 [Contig_View]  USP1 [Vega]
ICGC DataPortalENSG00000162607
TCGA cBioPortalUSP1
AceView (NCBI)USP1
Genatlas (Paris)USP1
SOURCE (Princeton)USP1
Genetics Home Reference (NIH)USP1
Genomic and cartography
GoldenPath hg38 (UCSC)USP1  -     chr1:62437049-62451804 +  1p31.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)USP1  -     1p31.3   [Description]    (hg19-Feb_2009)
GoldenPathUSP1 - 1p31.3 [CytoView hg19]  USP1 - 1p31.3 [CytoView hg38]
Genome Data Viewer NCBIUSP1 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AB014458 AB208893 AF117386 AK096788 AK312423
RefSeq transcript (Entrez)NM_001017415 NM_001017416 NM_003368
Consensus coding sequences : CCDS (NCBI)USP1
Gene ExpressionUSP1 [ NCBI-GEO ]   USP1 [ EBI - ARRAY_EXPRESS ]   USP1 [ SEEK ]   USP1 [ MEM ]
Gene Expression Viewer (FireBrowse)USP1 [ Firebrowse - Broad ]
GenevisibleExpression of USP1 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)7398
GTEX Portal (Tissue expression)USP1
Human Protein AtlasENSG00000162607-USP1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO94782   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO94782  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO94782
Domaine pattern : Prosite (Expaxy)USP_1 (PS00972)    USP_2 (PS00973)    USP_3 (PS50235)   
Domains : Interpro (EBI)Papain-like_cys_pep_sf    Peptidase_C19_UCH    USP1    USP_CS    USP_dom   
Domain families : Pfam (Sanger)UCH (PF00443)   
Domain families : Pfam (NCBI)pfam00443   
Conserved Domain (NCBI)USP1
PDB Europe6DO5   
PDB (PDBSum)6DO5   
PDB (IMB)6DO5   
Structural Biology KnowledgeBase6DO5   
SCOP (Structural Classification of Proteins)6DO5   
CATH (Classification of proteins structures)6DO5   
AlphaFold pdb e-kbO94782   
Human Protein Atlas [tissue]ENSG00000162607-USP1 [tissue]
Protein Interaction databases
IntAct (EBI)O94782
Ontologies - Pathways
Ontology : AmiGOskeletal system development  cysteine-type endopeptidase activity  thiol-dependent deubiquitinase  thiol-dependent deubiquitinase  thiol-dependent deubiquitinase  protein binding  nucleus  nucleus  nucleoplasm  nucleoplasm  cytosol  DNA repair  regulation of DNA repair  ubiquitin-dependent protein catabolic process  peptidase activity  response to UV  protein deubiquitination  protein deubiquitination  monoubiquitinated protein deubiquitination  
Ontology : EGO-EBIskeletal system development  cysteine-type endopeptidase activity  thiol-dependent deubiquitinase  thiol-dependent deubiquitinase  thiol-dependent deubiquitinase  protein binding  nucleus  nucleus  nucleoplasm  nucleoplasm  cytosol  DNA repair  regulation of DNA repair  ubiquitin-dependent protein catabolic process  peptidase activity  response to UV  protein deubiquitination  protein deubiquitination  monoubiquitinated protein deubiquitination  
REACTOMEO94782 [protein]
REACTOME PathwaysR-HSA-6783310 [pathway]   
NDEx NetworkUSP1
Atlas of Cancer Signalling NetworkUSP1
Wikipedia pathwaysUSP1
Orthology - Evolution
GeneTree (enSembl)ENSG00000162607
Phylogenetic Trees/Animal Genes : TreeFamUSP1
Homologs : HomoloGeneUSP1
Homology/Alignments : Family Browser (UCSC)USP1
Gene fusions - Rearrangements
Fusion : MitelmanUSP1::EFCAB7 [1p31.3/1p31.3]  
Fusion : MitelmanUSP1::SGIP1 [1p31.3/1p31.3]  
Fusion : FusionGDB3.4.19.12   
Fusion : FusionHubAGFG1--USP1    CACHD1--USP1    IL13RA1--USP1    PTBP2--USP1    SLC16A1--USP1    USP1--ADAM9    USP1--DOCK7    USP1--EFCAB7    USP1--EHMT1    USP1--GTF2F2   
USP1--INO80B    USP1--INO80B-WBP1    USP1--MIER1    USP1--NUCKS1    USP1--RNASEH2B    USP1--SGIP1    USP1--SKI    USP1--USP1   
Fusion : QuiverUSP1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerUSP1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)USP1
Exome Variant ServerUSP1
GNOMAD BrowserENSG00000162607
Varsome BrowserUSP1
ACMGUSP1 variants
Genomic Variants (DGV)USP1 [DGVbeta]
DECIPHERUSP1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisUSP1 
ICGC Data PortalUSP1 
TCGA Data PortalUSP1 
Broad Tumor PortalUSP1
OASIS PortalUSP1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICUSP1  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DUSP1
Mutations and Diseases : HGMDUSP1
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)USP1
DoCM (Curated mutations)USP1
CIViC (Clinical Interpretations of Variants in Cancer)USP1
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry USP1
NextProtO94782 [Medical]
Target ValidationUSP1
Huge Navigator USP1 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDUSP1
Pharm GKB GenePA37233
Clinical trialUSP1
DataMed IndexUSP1
PubMed99 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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