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Gene Section Review Atlas of Genetics and Cytogenetics in Oncology and Haematology INIST -CNRS OPEN ACCESS JOURNAL 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 Ubiquitin specific peptidase 1 is located at Review on USP1, with data on DNA/RNA, on the chromosome 1 in the region p31.3. USP1 was first protein encoded and where the gene is implicated. cloned in 1998 as part of the Human Genome Identity Project (Fujiwara et al., 1998). Transcription Other names: UBP USP1 transcription is controlled by different HGNC (Hugo): USP1 mechanisms. On one hand, USP1 mRNA levels Location: 1p31.3 fluctuate during the cell cycle, reaching a peak in S Local order: Based on Mapviewer, genes flanking phase, and remaining low before and after it USP1 are: (Nijman et al., 2005). On the other hand, DNA damaging agents can - L1TD1 (LINE-1 type transposase domain repress USP1 transcription by a mechanism that containing 1); 1p31.3 involves p21 cyclin dependent kinase inhibitor - ANKRD38 (ankyrin repeat domain 38); 1p31.3 (Rego et al., 2012). - USP1 (ubiquitin specific peptidase 1); 1p31.3 Transcription produces 10 different mRNAs, 6 - DOCK7 (dedicator of cytokinesis 7); 1p31.3 alternatively spliced variants and 4 unspliced forms. - ANGPTL3 (angiopoietin-like 3); 1p31.1-p22.3. There are 5 probable alternative promotors, 2 non overlapping alternative last exons and 9 validated DNA/RNA alternative polyadenylation sites. Note The mRNAs appear to differ by truncation of the 5' Structural organization of USP1 gene: USP1 end, overlapping exons with different boundaries. gene is located on chromosome 1. 3 transcripts of Efficacy of translation may be reduced by the this gene, encoding the same protein product, have presence of a shorter translated product (uORF) been identified. initiating at an AUG upstream of the main open The gene contains 14 distinct gt-ag introns. reading frame. 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/C Cdh1 -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) 351 USP1 (ubiquitin specific peptidase 1) García-Santisteban I, et al. Pseudogene subjected to proteasomal degradation (Huang et al., 2006; Piatkov et al., 2012). No reported pseudogenes. Paralogs for USP1 gene include USP12, USP35, USP38, and USP46. Localisation The localization of USP1 is nuclear. USP1 bears Protein two nuclear localization signals (NLSs) which Description mediate the import of the USP1/UAF1 complex to the cell nucleus, where it exerts its function USP1 gene encodes a 785 amino acid protein with a (García-Santisteban et al., 2012b). USP1 also predicted molecular weight of 88,2 kDa (Fujiwara contains a nuclear export signal (NES, not indicated et al., 1998). USP1 belongs to the ubiquitin specific in the figure) that was shown to be functional in an protease (USP) family of human deubiquitinases export assay, but whose function in the context of (DUBs). Like other members of its family, it the full length protein needs to be evaluated harbours a highly conserved USP domain (García-Santisteban et al., 2012a). organization comprising a N-terminal Cys box and a C-terminal His box, which contain the catalytic Function residues (C90, H593 and D751) (Fujiwara et al., USP1, together with UAF1, plays an important role 1998; Villamil et al., 2012a; Békés et al., 2013). in the DNA damage response, mainly in the The enzymatic activity of USP1 alone is relatively Fanconi anemia (FA) pathway and in the process of low, but is enhanced upon binding to USP1 translesion synthesis (TLS). Deubiquitination of associated factor 1 (UAF1) (Cohn et al., 2007; FANCD2 and FANCI by the USP1/UAF1 complex Villamil et al., 2012a). The UAF1 binding region in is an essential step for the correct function of the USP1 is somewhat controversial, since two binding FA pathway (Nijman et al., 2005; Sims et al., motifs have been proposed based on different 2007). In addition, the USP1/UAF1 complex experimental approaches. Villamil and co-workers mediates the deubiqutination of Proliferating Cell proposed that the UAF1 binding region comprised Nuclear Antigen (PCNA), preventing the residues 235-408 (Villamil et al., 2012b), but recruitment of low fidelity DNA polymerases in the García-Santisteban et al. described that the binding absence of DNA damage (Huang et al., 2006). motif was between amino acid residues 420-520 In addition to its DNA damage-related functions, (García-Santisteban et al., 2012a). Further USP1 has also been reported to deubiquitinate and experimental evidence should clarify this stabilize three members of the family of inhibitors controversy. of DNA binding (ID) proteins (ID1, ID2 and ID3), Expression and thus contributing to preserve the undifferentiated state of osteosarcoma cells USP1 protein levels can be regulated through (Williams et al., 2011). different mechanisms that involve proteasome mediated degradation. On one hand, anaphase Homology Cdh1 Cdh1 promoting complex/cyclosome (APC/C ) The USP1 gene is conserved in chimpanzee, recognizes the 295-342 amino acid region (Degron) Rhesus monkey, dog, cow, mouse, rat, chicken, in USP1, mediating its degradation by the zebrafish, fruit fly, and mosquito. proteasome (Cotto-Rios et al., 2011a). The serine 313 residue located in this region is phosphorylated Mutations by cyclin dependent kinases (CDKs), which might prevent USP1 degradation in mitosis (Cotto-Rios et Note al., 2011b). On the other hand, UV damage causes A survey in the COSMIC mutation database USP1 autocleavage at an internal diglycine motif (accession date: 16 September 2013) revealed a (Gly-Gly) located in the C-terminal end of the total of 40 mutations that lead to different protein. The resulting USP1 fragments are modifications in different human tumors. Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 352 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. Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 353 USP1 (ubiquitin specific peptidase 1) García-Santisteban I, et al. Most of the modifications are missense mutations Disruption of the USP1 gene in mice results in whose functional consequences need to be genomic instability and FA phenotype, and also addressed. leads to defects in hematopoietic stem cell maintenance (Kim et al., 2009; Parmar et al., 2010). Implicated in Osteosarcoma To be noted Note Note A recent study showed that USP1 mRNA and This work was supported by the Basque Country protein levels were elevated in a subset of primary Government Department of Industry (grant number osteosarcoma tumors, and that increased USP1 ETORTEK BioGUNE2010 to JAR), the Spanish levels correlated with increased levels of its Government MICINN (Ministerio de Ciencia e substrate ID2. This observation is consistent with Innovacion) (grant number BFU2009-13245 to the finding that USP1 deubiquitinates and stabilizes JAR), the University of the Basque Country ID proteins, contributing to preserve the (UFI11/20), Department of Education of the undifferentiated state of osteosarcoma cells. Basque Country Government Fellowship (to IG-S), the Netherlands Organization for Scientific Cytogenetics Research, Veni grant (to EG) and CCA Foundation Comparative genomic hybridization (CGH) (grant number 2012-5-07 to EG and GJP). analyses found that the USP1 locus 1p31.3 was amplified in 26%-57% of osteosarcoma tumors (Ozaki et al., 2003; Stock et al., 2000). References Lung cancer Fujiwara T, Saito A, Suzuki M, Shinomiya H, Suzuki T, Takahashi E, Tanigami A, Ichiyama A, Chung CH, Note Nakamura Y, Tanaka K. Identification and chromosomal One study reported lower USP1 mRNA and protein assignment of USP1, a novel gene encoding a human levels in lung cancer cells and tissues (Zhiqiang et ubiquitin-specific protease. Genomics. 1998 Nov 15;54(1):155-8 al., 2012). However, most data support the view that USP1 is overexpressed in lung cancer. Thus, a Stock C, Kager L, Fink FM, Gadner H, Ambros PF. Chromosomal
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