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• W3013703016 abstract "Abstract BRCA1 gene mutations impair homologous recombination (HR) DNA repair, resulting in cellular senescence and embryonic lethality in mice. Therefore, BRCA1-deficient cancers require adaptations that prevent excessive genomic alterations from triggering cell death. RNF168-mediated ubiquitination of γH2AX at K13/15 (ub-H2AX) serves as a recruitment module for the localization of 53BP1 to DNA break sites. Here, we found multiple BRCA1-mutant cancer cell lines and primary tumors with low levels of RNF168 protein expression. Overexpression of ectopic RNF168 or a ub-H2AX fusion protein induced cell death and delayed BRCA1-mutant tumor formation. Cell death resulted from the recruitment of 53BP1 to DNA break sites and inhibition of DNA end resection. Strikingly, reintroduction of BRCA1 or 53BP1 depletion restored HR and rescued the ability of cells to maintain RNF168 and ub-H2AX overexpression. Thus, downregulation of RNF168 protein expression is a mechanism for providing BRCA1-null cancer cell lines with a residual level of HR that is essential for viability. Overall, our work identifies loss of RNF168 ubiquitin signaling as a proteomic alteration that supports BRCA1-mutant carcinogenesis. We propose that restoring RNF168-ub-H2AX signaling, potentially through inhibition of deubiquitinases, could represent a new therapeutic approach. Significance: This study explores the concept that homologous recombination DNA repair is not an all-or-nothing concept, but a spectrum, and that where a tumor stands on this spectrum may have therapeutic relevance. See related commentary by Wang and Wulf, p. 2720" @default.
• W3013703016 created "2020-04-03" @default.
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• W3013703016 date "2020-07-01" @default.
• W3013703016 modified "2023-10-11" @default.
• W3013703016 title "RNF168-Mediated Ubiquitin Signaling Inhibits the Viability of <i>BRCA1</i>-Null Cancers" @default.
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• W3013703016 doi "https://doi.org/10.1158/0008-5472.can-19-3033" @default.
• W3013703016 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7335334" @default.
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