Department of Oncology, Genome Stability and Tumorigenesis Group, The CR-UK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
Area of Translational Research, Regina Elena National Cancer Institute, Rome, Italy.
EMBO Mol Med. 2017 Oct;9(10):1398-1414. doi: 10.15252/emmm.201607446.
Maintenance of genome integrity requires the functional interplay between Fanconi anemia (FA) and homologous recombination (HR) repair pathways. Endogenous acetaldehyde, a product of cellular metabolism, is a potent source of DNA damage, particularly toxic to cells and mice lacking the FA protein FANCD2. Here, we investigate whether HR-compromised cells are sensitive to acetaldehyde, similarly to FANCD2-deficient cells. We demonstrate that inactivation of HR factors BRCA1, BRCA2, or RAD51 hypersensitizes cells to acetaldehyde treatment, in spite of the FA pathway being functional. Aldehyde dehydrogenases (ALDHs) play key roles in endogenous acetaldehyde detoxification, and their chemical inhibition leads to cellular acetaldehyde accumulation. We find that disulfiram (Antabuse), an ALDH2 inhibitor in widespread clinical use for the treatment of alcoholism, selectively eliminates BRCA1/2-deficient cells. Consistently, gene inactivation suppresses proliferation of HR-deficient mouse embryonic fibroblasts (MEFs) and human fibroblasts. Hypersensitivity of cells lacking BRCA2 to acetaldehyde stems from accumulation of toxic replication-associated DNA damage, leading to checkpoint activation, G2/M arrest, and cell death. Acetaldehyde-arrested replication forks require BRCA2 and FANCD2 for protection against MRE11-dependent degradation. Importantly, acetaldehyde specifically inhibits the growth of BRCA1/2-deficient tumors and in patient-derived tumor xenograft cells (PDTCs), including those that are resistant to poly (ADP-ribose) polymerase (PARP) inhibitors. The work presented here therefore identifies acetaldehyde metabolism as a potential therapeutic target for the selective elimination of BRCA1/2-deficient cells and tumors.
维持基因组完整性需要范可尼贫血症 (FA) 和同源重组 (HR) 修复途径之间的功能相互作用。细胞代谢产生的内源性乙醛是 DNA 损伤的一个强有力来源，对缺乏 FA 蛋白 FANCD2 的细胞和老鼠尤其有毒。在这里，我们研究了 HR 受损的细胞是否像 FANCD2 缺陷细胞一样对乙醛敏感。我们证明，尽管 FA 途径是功能性的，但 HR 因子 BRCA1、BRCA2 或 RAD51 的失活会使细胞对乙醛处理敏感。醛脱氢酶 (ALDHs) 在体内乙醛解毒中发挥关键作用，其化学抑制会导致细胞内乙醛积累。我们发现，临床上广泛用于治疗酗酒的 ALDH2 抑制剂安塔布司（Disulfiram）选择性消除 BRCA1/2 缺陷细胞。一致地，基因失活抑制 HR 缺陷的小鼠胚胎成纤维细胞 (MEFs) 和人成纤维细胞的增殖。BRCA2 缺陷细胞对乙醛的超敏感性源于有毒复制相关 DNA 损伤的积累，导致检查点激活、G2/M 期阻滞和细胞死亡。缺乏 BRCA2 的细胞中，乙醛阻滞的复制叉需要 BRCA2 和 FANCD2 来防止 MRE11 依赖性降解。重要的是，乙醛特异性抑制 BRCA1/2 缺陷肿瘤的生长，并抑制患者来源的肿瘤异种移植物细胞（PDTCs）的生长，包括对聚（ADP-核糖）聚合酶 (PARP) 抑制剂耐药的肿瘤。因此，这里介绍的工作确定了乙醛代谢作为一种潜在的治疗靶点，用于选择性消除 BRCA1/2 缺陷细胞和肿瘤。
