Usp7 protects genomic stability by regulating Bub3

Serena Giovinazzi; Pietro Sirleto; Vasilisa Aksenova; Viacheslav M. Morozov; Roberto Zori; William C. Reinhold; Alexander M. Ishov

doi:10.18632/oncotarget.1989

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Research Papers:

Usp7 protects genomic stability by regulating Bub3

Serena Giovinazzi, Pietro Sirleto, Vasilisa Aksenova, Viacheslav M. Morozov, Roberto Zori, William C. Reinhold and Alexander M. Ishov _

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Oncotarget. 2014; 5:3728-3742. https://doi.org/10.18632/oncotarget.1989

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Abstract

Serena Giovinazzi1,2, Pietro Sirleto3, Vasilisa Aksenova4, Viacheslav M. Morozov1,2, Roberto Zori5, William C. Reinhold6 and Alexander M. Ishov1,2

1 Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL

2 University of Florida Health Cancer Center, Gainesville, FL

3 Bambino Gesu’ Children’s Hospital, Rome, Italy

4 Molecular Pharmacology laboratory, Institute of Technology and Institute of Cytology, St-Petersburg, Russia

5 Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL

6 Genomics and Bioinformatics Group, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD

Correspondence:

Alexander M. Ishov, email:

Keywords: deubiquitinase USP7, Bub3, spindle assembly checkpoint (SAC), genomic instability, USP7 inhibitors

Received: April 15, 2014 Accepted: May 17, 2014 Published: May 19, 2014

Abstract

USP7 (Ubiquitin Specific processing Protease-7) is a deubiquitinase which, over the past decade emerged as a critical regulator of cellular processes. Deregulation of USP7 activity has been linked to cancer, making USP7 inhibition an appealing anti-cancer strategy. The identification of novel USP7 substrates and additional USP7-dependent cellular activities will broaden our knowledge towards potential clinical application of USP7 inhibitors. Results presented in this study uncover a novel and pivotal function of USP7 in the maintenance of genomic stability. Upon USP7 depletion we observed prolonged mitosis and mitotic abnormalities including micronuclei accumulation, lagging chromosomes and karyotype instability. Inhibition of USP7 with small molecule inhibitors stabilizes cyclin B and causes mitotic abnormalities. Our results suggest that these USP7-dependent effects are mediated by decreased levels of spindle assembly checkpoint (SAC) component Bub3, which we characterized as an interacting partner and substrate of USP7. In silico analysis across the NCI-60 panels of cell lines supports our results where lower levels of USP7 strongly correlate with genomic instability. In conclusion, we identified a novel role of USP7 as regulator of the SAC component Bub3 and genomic stability.

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Research Papers:

Usp7 protects genomic stability by regulating Bub3

Abstract