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

Hernandez-Perez, S., Cabrera, E., Salido, E., Lim, M., Reid, L., Lakhani, S. R., Khanna, K. K., Saunus, J. M. and Freire, R. (2017) DUB3 and USP7 de-ubiquitinating enzymes control replication inhibitor Geminin: molecular characterization and associations with breast cancer. Oncogene, 36 33: 4802-4809. doi:10.1038/onc.2017.21


Author Hernandez-Perez, S.
Cabrera, E.
Salido, E.
Lim, M.
Reid, L.
Lakhani, S. R.
Khanna, K. K.
Saunus, J. M.
Freire, R.
Title DUB3 and USP7 de-ubiquitinating enzymes control replication inhibitor Geminin: molecular characterization and associations with breast cancer
Journal name Oncogene   Check publisher's open access policy
ISSN 1476-5594
0950-9232
Publication date 2017-03-13
Sub-type Article (original research)
DOI 10.1038/onc.2017.21
Open Access Status Not Open Access
Volume 36
Issue 33
Start page 4802
End page 4809
Total pages 8
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Abstract 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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