BRCA1/2变异与乳腺癌高发和对当前治疗方法（包括PARP抑制剂）的耐药性常有关联。鉴于缺乏针对BRCA1突变癌症的有效靶向治疗方法，我们试图找到能选择性杀灭这些癌细胞的新靶点。在这里，我们报告了RNF8缺失在Brca1突变小鼠中能显著保护其免受乳腺肿瘤发生的影响。在人类BRCA1突变乳腺癌细胞中，发现RNF8缺失能促进R环堆积和复制叉不稳定性，导致DNA损伤、细胞衰老和合成致死效应。机制上，RNF8与关键的转录终止和R环解析相关的XRN2发生相互作用。我们报告了RNF8泛素化XRN2以促进其招募到易于出现R环的基因组位点，并且在BRCA1突变乳腺癌细胞中，RNF8缺失减少了XRN2在易于形成R环位点的占位，从而促进了R环的积累、转录 - 复制冲突、过度的基因组不稳定性和癌细胞死亡。综上所述，我们的研究确定了RNF8与BRCA1之间的合成功用致死作用，并且这种作用是由于R环的病理性积累所介导的。© 2023年作者授予牛津大学出版社的《核酸研究》发表许可。

Breast cancer linked with BRCA1/2 mutations commonly recur and resist current therapies, including PARP inhibitors. Given the lack of effective targeted therapies for BRCA1-mutant cancers, we sought to identify novel targets to selectively kill these cancers. Here, we report that loss of RNF8 significantly protects Brca1-mutant mice against mammary tumorigenesis. RNF8 deficiency in human BRCA1-mutant breast cancer cells was found to promote R-loop accumulation and replication fork instability, leading to increased DNA damage, senescence, and synthetic lethality. Mechanistically, RNF8 interacts with XRN2, which is crucial for transcription termination and R-loop resolution. We report that RNF8 ubiquitylates XRN2 to facilitate its recruitment to R-loop-prone genomic loci and that RNF8 deficiency in BRCA1-mutant breast cancer cells decreases XRN2 occupancy at R-loop-prone sites, thereby promoting R-loop accumulation, transcription-replication collisions, excessive genomic instability, and cancer cell death. Collectively, our work identifies a synthetic lethal interaction between RNF8 and BRCA1, which is mediated by a pathological accumulation of R-loops.© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.