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][1] [1]: /lookup/volpage/80/2720?iss=13

中文翻译：

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RNF168介导的泛素信号传导抑制BRCA1无效癌症的生存能力。

BRCA1基因突变损害同源重组（HR）DNA修复，导致小鼠细胞衰老和胚胎致死率。因此，BRCA1缺陷型癌症需要适应性治疗，以防止过度的基因组改变触发细胞死亡。RNF168介导的K13 / 15上的γH2AX泛素化（ub-H2AX）作为募集模块，用于将53BP1定位到DNA断裂位点。在这里，我们发现了多个BRCA1突变癌细胞系和RNF168蛋白表达水平较低的原发肿瘤。异位RNF168或ub-H2AX融合蛋白的过表达诱导细胞死亡并延迟BRCA1突变肿瘤的形成。细胞死亡是由53BP1募集到DNA断裂位点和DNA末端切除的抑制导致的。惊人地 再次引入BRCA1或53BP1耗竭可恢复HR，并挽救细胞维持RNF168和ub-H2AX过表达的能力。因此，RNF168蛋白表达的下调是一种为BRCA1无效的癌细胞系提供残存的HR水平的机制，HR对于生存力是必不可少的。总的来说，我们的工作将RNF168泛素信号传导的缺失确定为支持BRCA1突变致癌作用的蛋白质组学改变。我们建议恢复RNF168-ub-H2AX信号，可能通过抑制去泛素酶来代表一种新的治疗方法。启示：这项研究探索了一个概念，即同源重组DNA修复不是一个全有或全无的概念，而是一个光谱，并且肿瘤位于该光谱上的位置可能具有治疗意义。参见Wang和Wulf的相关评论，[p。2720] [1] [1]：