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Oncogene. 2017 Aug 17;36(33):4802-4809. doi: 10.1038/onc.2017.21. Epub 2017 Mar 13.

DUB3 and USP7 de-ubiquitinating enzymes control replication inhibitor Geminin: molecular characterization and associations with breast cancer.

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Unidad de Investigación, Hospital Universitario de Canarias, Instituto de Tecnologías Biomédicas, La Laguna, Spain.
The University of Queensland, UQ Centre for Clinical Research, Herston, QLD, Australia.
QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
Pathology Queensland, The Royal Brisbane and Women's Hospital, Herston, QLD, Australia.
The University of Queensland, School of Medicine, Herston, QLD, Australia.
Signal Transduction Laboratory, QIMR Berghofer Institute of Medical Research, Brisbane, QLD, Australia.


Correct control of DNA replication is crucial to maintain genomic stability in dividing cells. Inappropriate re-licensing of replicated origins is associated with chromosomal instability (CIN), a hallmark of cancer progression that at the same time provides potential opportunities for therapeutic intervention. Geminin is a critical inhibitor of the DNA replication licensing factor Cdt1. To properly achieve its functions, Geminin levels are tightly regulated through the cell cycle by ubiquitin-dependent proteasomal degradation, but the de-ubiquitinating enzymes (DUBs) involved had not been identified. Here we report that DUB3 and USP7 control human Geminin. Overexpression of either DUB3 or USP7 increases Geminin levels through reduced ubiquitination. Conversely, depletion of DUB3 or USP7 reduces Geminin levels, and DUB3 knockdown increases re-replication events, analogous to the effect of Geminin depletion. In exploring potential clinical implications, we found that USP7 and Geminin are strongly correlated in a cohort of invasive breast cancers (P<1.01E-08). As expected, Geminin expression is highly prognostic. Interestingly, we found a non-monotonic relationship between USP7 and breast cancer-specific survival, with both very low or high levels of USP7 associated with poor outcome, independent of estrogen receptor status. Altogether, our data identify DUB3 and USP7 as factors that regulate DNA replication by controlling Geminin protein stability, and suggest that USP7 may be involved in Geminin dysregulation during breast cancer progression.

[Indexed for MEDLINE]

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