USP1 (ubiquitin specific peptidase 1)

	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.

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