Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Cell Rep. 2020 Feb 4;30(5):1385-1399.e7. doi: 10.1016/j.celrep.2020.01.020.
The Mre11-Rad50-Nbs1 complex is a DNA double-strand break sensor that mediates a tumor-suppressive DNA damage response (DDR) in cells undergoing oncogenic stress, yet the mechanisms underlying this effect are poorly understood. Using a genetically inducible primary mammary epithelial cell model, we demonstrate that Mre11 suppresses proliferation and DNA damage induced by diverse oncogenic drivers through a p53-independent mechanism. Breast tumorigenesis models engineered to express a hypomorphic Mre11 allele exhibit increased levels of oncogene-induced DNA damage, R-loop accumulation, and chromosomal instability with a characteristic copy number loss phenotype. Mre11 complex dysfunction is identified in a subset of human triple-negative breast cancers and is associated with increased sensitivity to DNA-damaging therapy and inhibitors of ataxia telangiectasia and Rad3 related (ATR) and poly (ADP-ribose) polymerase (PARP). Thus, deficiencies in the Mre11-dependent DDR drive proliferation and genome instability patterns in p53-deficient breast cancers and represent an opportunity for therapeutic exploitation.
Mre11-Rad50-Nbs1 复合物是一种 DNA 双链断裂传感器，可介导发生致癌应激的细胞中的肿瘤抑制性 DNA 损伤反应 (DDR)，但其作用机制尚不清楚。使用遗传诱导的原代乳腺上皮细胞模型，我们证明 Mre11 通过一种不依赖 p53 的机制抑制多种致癌驱动因素诱导的增殖和 DNA 损伤。表达低功能 Mre11 等位基因的乳腺癌肿瘤发生模型表现出更高水平的致癌基因诱导的 DNA 损伤、R 环积累和染色体不稳定性，具有特征性的拷贝数缺失表型。在一部分人类三阴性乳腺癌中发现了 Mre11 复合物功能障碍，并且与对 DNA 损伤治疗和共济失调毛细血管扩张症和 Rad3 相关 (ATR) 和聚 (ADP-核糖) 聚合酶 (PARP) 抑制剂的敏感性增加有关。因此，Mre11 依赖性 DDR 的缺陷会驱动 p53 缺陷型乳腺癌中的增殖和基因组不稳定性模式，代表了治疗利用的机会。
