Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 1L7, Canada.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Nucleic Acids Res. 2023 Oct 27;51(19):10484-10505. doi: 10.1093/nar/gkad733.
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.
乳腺癌与 BRCA1/2 突变通常会复发并抵抗当前的治疗方法，包括 PARP 抑制剂。鉴于缺乏针对 BRCA1 突变癌症的有效靶向治疗方法，我们试图寻找新的靶点来选择性地杀死这些癌症。在这里，我们报告 RNF8 的缺失显著保护 Brca1 突变小鼠免受乳腺肿瘤发生。发现在人类 BRCA1 突变型乳腺癌细胞中缺乏 RNF8 会促进 R 环积累和复制叉不稳定，导致 DNA 损伤、衰老和合成致死。在机制上，RNF8 与 XRN2 相互作用，XRN2 对于转录终止和 R 环解析至关重要。我们报告 RNF8 泛素化 XRN2 以促进其募集到 R 环易位的基因组位置，并且 BRCA1 突变型乳腺癌细胞中 RNF8 的缺失会降低 XRN2 在 R 环易位部位的占有率，从而促进 R 环积累、转录-复制碰撞、过度基因组不稳定性和癌细胞死亡。总的来说，我们的工作确定了 RNF8 和 BRCA1 之间的合成致死相互作用，这是由 R 环的病理性积累介导的。
