USP1 deubiquitinase: cellular functions, regulatory mechanisms and emerging potential as target in cancer therapy

Abstract

Reversible protein ubiquitination is emerging as a key process for maintaining cell homeostasis, and the enzymes that participate in this process, in particular E3 ubiquitin ligases and deubiquitinases (DUBs), are increasingly being regarded as candidates for drug discovery. Human DUBs are a group of approximately 100 proteins, whose cellular functions and regulatory mechanisms remain, with some exceptions, poorly characterized. One of the best-characterized human DUBs is ubiquitin-specific protease 1 (USP1), which plays an important role in the cellular response to DNA damage. USP1 levels, localization and activity are modulated through several mechanisms, including protein-protein interactions, autocleavage/degradation and phosphorylation, ensuring that USP1 function is carried out in a properly regulated spatio-temporal manner. Importantly, USP1 expression is deregulated in certain types of human cancer, suggesting that USP1 could represent a valid target in cancer therapy. This view has gained recent support with the finding that USP1 inhibition may contribute to revert cisplatin resistance in an in vitro model of non-small cell lung cancer (NSCLC). Here, we describe the current knowledge on the cellular functions and regulatory mechanisms of USP1. We also summarize USP1 alterations found in cancer, combining data from the literature and public databases with our own data. Finally, we discuss the emerging potential of USP1 as a target, integrating published data with our novel findings on the effects of the USP1 inhibitor pimozide in combination with cisplatin in NSCLC cells.

The identification of translesion DNA synthesis regulators: Inhibitors in the spotlight

“…Interestingly, USP1 also de-ubiquitinates FANCD2, a key member of the Fanconi Anemia (FA) pathway, required for the repair of DNA interstrand crosslinks (ICLs). The loss of the FA pathway causes multiple abnormalities leading to cancer, which correlate with USP1 overexpression in several tumour types [41]. Given the utmost importance of the FA pathway during DDR, the inability to separate the contribution of USP1 to FANCD2- and PCNA-dependent signalling complicates the identification of the direct contribution of USP1 to TLS signalling.…”

A novel role for the deubiquitinase USP1 in the control of centrosome duplication

“…[23][24][25] Interestingly, a search of an integrated cancer microarray database (Oncomine) revealed that USP1 is overexpressed in several tumor types including cervical, gastric cancer, melanoma and sarcoma. 26,27 However, little is known about the significance of USP1 overexpression in tumorigenesis.…”

“…29 USP44 regulates centrosome positioning to prevent aneuploidy and suppress tumorigenesis. 30 Given that increased levels of USP1 are detected in certain types of human cancer, 26,27 we therefore tested if USP1 is involved in centrosome maintenance and exerts its oncogenic activity in part through centrosomal function.…”

The Ubiquitin-Proteasome System (UPS) as a Cancer Drug Target: Emerging Mechanisms and Therapeutics

“…248 chemotherapy drug cisplatin to inhibit the proliferation of cisplatin-resistant non-small cell lung cancer (NSCLC) cells (Chen et al 2011 ;Garcia-Santisteban et al 2013 ). One company, Hybrigenics, has developed a variety of different inhibitors of the USP family (Table 11.3 ).…”