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.
Highlights
Ubiquitin is a 76 amino acid long peptide that can be covalently attached to proteins to modulate their stability, localization or function
The important regulatory role of ubiquitin-specific protease 1 (USP1) in DNA repair, supported by the finding that USP1 gene knockout in model systems leads to DNA damage hypersensitivity [62,63,64], together with the observation that USP1 is frequently overexpressed in tumors, suggests that USP1 could be a relevant target for cancer therapy, whose inhibition might contribute to overcome chemoresistance
This view has recently gained experimental support with the identification of two compounds that inhibit the activity of the USP1/USP1-associated factor 1 (UAF1) complex, and reverse the resistance of non-small cell lung cancer (NSCLC) cells to cisplatin [94], a DNA damaging drug commonly used in cancer chemotherapy
Summary
Ubiquitin is a 76 amino acid long peptide that can be covalently attached to proteins to modulate their stability, localization or function. It is becoming increasingly clear that the DDR is critically regulated by ubiquitination and deubiquitination, and the concept has evolved that targeting the enzymes that play a role in these processes, including DUBs [19,49,50,51], might be an approach to overcome resistance to conventional therapy [40] It has been suggested, for example, that inhibition of USP7, a DUB that functions in the G2/M checkpoint triggered by DNA damage, might improve treatment efficiency when used in combination with a genotoxic agent [42]. Monoubiquitinated FANCD2 (ubFANCD2) and FANCI (ub-FANCI) serve as a platform to
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