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.

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/cyclosome^Cdh1 (APC/C^Cdh1) 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.