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.
Highlights
As it was first postulated by the German biologist Theodor Boveri in 1902, the precise partitioning of duplicated chromosomes to daughter cells is essential for the development and survival of all organisms
We identified a new biological role of USP7 in G2/M progression and characterized Bub3 as a USP7 interaction partner and a USP7 substrate
We presented evidence for a novel, p53-independent, role of USP7 in maintenance of genomic stability, suggesting a tumor suppressor function for this protein
Summary
As it was first postulated by the German biologist Theodor Boveri in 1902, the precise partitioning of duplicated chromosomes to daughter cells is essential for the development and survival of all organisms. Abnormal attachments (syntelic or merotelic) must be corrected so that until all chromosomes are under proper tension and bi-orientation, the metaphaseanaphase transition is delayed [9, 10] In eukaryotic cells this delicate mission is assigned to the Spindle Assembly Checkpoint (SAC) [11]. To the SAC belongs a long list of proteins [12] that survey, detect and correct failed or improper microtubule/kinetochore attachments This system prevents segregation errors by inhibiting APC/ CCdc mediated destruction of cyclin B and securin, thereby blocking anaphase entrance. Drop in securin levels lift the inhibition on the cysteine protease separase This enzyme cleaves the cohesin rings which hold sister chromatids together, to initiate metaphase to anaphase transition [14]
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