Usp7 protects genomic stability by regulating Bub3

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.

USP11 deubiquitinates RAE1 and plays a key role in bipolar spindle formation

“…USP11 is not the first DUB shown to affect mitotic spindle formation. Indeed, confirming previous reports [ 34 , 44 ], we observed a dramatic increase in multipolar spindles upon ablation of USP7. Moreover, Yan and colleagues reported that the BRCC36 isopeptidase complex (BRICS), like USP11 is associated with microtubules, but influences mitotic spindle assembly by deubiquitinating NuMA [ 45 ].…”

“…As Giovanizzi et al . [ 34 ] reported, knock-down of USP7 resulted in a significant increase in multipolar spindles ( Fig 6G and 6I ). However, unlike USP11, USP7 ablation did not rescue the NuMA shRNA induced phenotype ( Fig 6H and 6J ).…”

“…It will be important to identify the E3 ligase that is responsible for ubiquitinating RAE1 and to determine the spatio- and temporal dynamics of this process. Moreover, it is intriguing that USP7 and USP11 associate with each other in the cell ([ 7 , 27 ] and this work), influence similar processes ([ 34 ] and this work) yet do so by using different substrates.…”

Targeting ubiquitin specific protease 7 in cancer: A deubiquitinase with great prospects

“…It is involved in spindle checkpoint function and inhibits the ubiquitin ligase activity of APC/C. Destabilization of Budding Uninhibited By Benzimidazoles 3 by USP7 leads to genomic instability by prolonging mitosis and mitotic abnormalities, causing micronuclei accumulation and increased aneuploidy . Another checkpoint protein, CHFR (checkpoint protein with FHA and RING domains), a RING family ubiquitin ligase induces the proteasome‐dependent degradation of a number of cellular proteins and helps in cell cycle progression .…”

Deubiquitinases and the new therapeutic opportunities offered to cancer

“…2008 ). USP7 also plays important roles in genomic stability by deubiquitinating and stabilizing many proteins involved in these pathways including BUB3 ( Giovinazzi et al . 2014 ), claspin ( Faustrup et al .…”