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

García-Santisteban I, Peters GJ, Giovannetti E, Rodríguez JA - Mol. Cancer (2013)

Bottom Line: Importantly, USP1 expression is deregulated in certain types of human cancer, suggesting that USP1 could represent a valid target in cancer therapy.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, Leioa, Spain.

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.

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USP1 Domain structure and summary of the cellular functions of the USP1/UAF1 complex. A. Shematic representation of USP1 protein showing the position of its amino-terminal Cys box and carboxy-terminal His box domains. The catalytic residues Cys90, His593 and Asp751 are indicated by arrowheads. B. Models illustrating the role of the USP1/UAF1 complex as regulator of three different cellular processes. In the Fanconi anemia (FA) pathway (upper panel), the FA core complex monoubiquitinates FANCD2 and FANCI, which mediate the recruitment of other proteins that repair DNA interstrand crosslink (ICL) lesions. USP1/UAF1 antagonizes the FA core complex deubiquitinating FANCD2 and FANCI. In the process of translesion synthesis (TLS) (middle panel), monoubiquitinated PCNA recruits specific TLS DNA polymerases that may bypass DNA lesions, but have lower fidelity than replicative polymerases. USP1/UAF1 may prevent unscheduled recruitment of low fidelity TLS polymerases by deubiquitinating PCNA. Finally (lower panel), USP1/UAF1 contributes to the maintaince of the undifferentiated state of osteosarcoma cells by promoting deubiquitination and stability of ID proteins, which, in turn, negatively regulate differentiation-inducing bHLH transcription factors.
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Figure 1: USP1 Domain structure and summary of the cellular functions of the USP1/UAF1 complex. A. Shematic representation of USP1 protein showing the position of its amino-terminal Cys box and carboxy-terminal His box domains. The catalytic residues Cys90, His593 and Asp751 are indicated by arrowheads. B. Models illustrating the role of the USP1/UAF1 complex as regulator of three different cellular processes. In the Fanconi anemia (FA) pathway (upper panel), the FA core complex monoubiquitinates FANCD2 and FANCI, which mediate the recruitment of other proteins that repair DNA interstrand crosslink (ICL) lesions. USP1/UAF1 antagonizes the FA core complex deubiquitinating FANCD2 and FANCI. In the process of translesion synthesis (TLS) (middle panel), monoubiquitinated PCNA recruits specific TLS DNA polymerases that may bypass DNA lesions, but have lower fidelity than replicative polymerases. USP1/UAF1 may prevent unscheduled recruitment of low fidelity TLS polymerases by deubiquitinating PCNA. Finally (lower panel), USP1/UAF1 contributes to the maintaince of the undifferentiated state of osteosarcoma cells by promoting deubiquitination and stability of ID proteins, which, in turn, negatively regulate differentiation-inducing bHLH transcription factors.

Mentions: The USP1 gene, cloned in 1998, encodes a 785 amino acid protein with a predicted molecular weight of 88.2 KDa [52]. USP1 bears the conserved USP domain that characterizes this DUB family, with an amino-terminal Cys box motif and a carboxy-terminal His box motif that contain the catalytic residues (Cys90, His593 and Asp751) [52-54] (Figure 1A).


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

García-Santisteban I, Peters GJ, Giovannetti E, Rodríguez JA - Mol. Cancer (2013)

USP1 Domain structure and summary of the cellular functions of the USP1/UAF1 complex. A. Shematic representation of USP1 protein showing the position of its amino-terminal Cys box and carboxy-terminal His box domains. The catalytic residues Cys90, His593 and Asp751 are indicated by arrowheads. B. Models illustrating the role of the USP1/UAF1 complex as regulator of three different cellular processes. In the Fanconi anemia (FA) pathway (upper panel), the FA core complex monoubiquitinates FANCD2 and FANCI, which mediate the recruitment of other proteins that repair DNA interstrand crosslink (ICL) lesions. USP1/UAF1 antagonizes the FA core complex deubiquitinating FANCD2 and FANCI. In the process of translesion synthesis (TLS) (middle panel), monoubiquitinated PCNA recruits specific TLS DNA polymerases that may bypass DNA lesions, but have lower fidelity than replicative polymerases. USP1/UAF1 may prevent unscheduled recruitment of low fidelity TLS polymerases by deubiquitinating PCNA. Finally (lower panel), USP1/UAF1 contributes to the maintaince of the undifferentiated state of osteosarcoma cells by promoting deubiquitination and stability of ID proteins, which, in turn, negatively regulate differentiation-inducing bHLH transcription factors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750636&req=5

Figure 1: USP1 Domain structure and summary of the cellular functions of the USP1/UAF1 complex. A. Shematic representation of USP1 protein showing the position of its amino-terminal Cys box and carboxy-terminal His box domains. The catalytic residues Cys90, His593 and Asp751 are indicated by arrowheads. B. Models illustrating the role of the USP1/UAF1 complex as regulator of three different cellular processes. In the Fanconi anemia (FA) pathway (upper panel), the FA core complex monoubiquitinates FANCD2 and FANCI, which mediate the recruitment of other proteins that repair DNA interstrand crosslink (ICL) lesions. USP1/UAF1 antagonizes the FA core complex deubiquitinating FANCD2 and FANCI. In the process of translesion synthesis (TLS) (middle panel), monoubiquitinated PCNA recruits specific TLS DNA polymerases that may bypass DNA lesions, but have lower fidelity than replicative polymerases. USP1/UAF1 may prevent unscheduled recruitment of low fidelity TLS polymerases by deubiquitinating PCNA. Finally (lower panel), USP1/UAF1 contributes to the maintaince of the undifferentiated state of osteosarcoma cells by promoting deubiquitination and stability of ID proteins, which, in turn, negatively regulate differentiation-inducing bHLH transcription factors.
Mentions: The USP1 gene, cloned in 1998, encodes a 785 amino acid protein with a predicted molecular weight of 88.2 KDa [52]. USP1 bears the conserved USP domain that characterizes this DUB family, with an amino-terminal Cys box motif and a carboxy-terminal His box motif that contain the catalytic residues (Cys90, His593 and Asp751) [52-54] (Figure 1A).

Bottom Line: Importantly, USP1 expression is deregulated in certain types of human cancer, suggesting that USP1 could represent a valid target in cancer therapy.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, Leioa, Spain.

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.

Show MeSH
Related in: MedlinePlus