人类细胞对 DNA 损伤反应的遗传图谱。
A Genetic Map of the Response to DNA Damage in Human Cells.
机构信息
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, M5G 1X5, Canada.
出版信息
Cell. 2020 Jul 23;182(2):481-496.e21. doi: 10.1016/j.cell.2020.05.040. Epub 2020 Jul 9.
The response to DNA damage is critical for cellular homeostasis, tumor suppression, immunity, and gametogenesis. In order to provide an unbiased and global view of the DNA damage response in human cells, we undertook 31 CRISPR-Cas9 screens against 27 genotoxic agents in the retinal pigment epithelium-1 (RPE1) cell line. These screens identified 890 genes whose loss causes either sensitivity or resistance to DNA-damaging agents. Mining this dataset, we discovered that ERCC6L2 (which is mutated in a bone-marrow failure syndrome) codes for a canonical non-homologous end-joining pathway factor, that the RNA polymerase II component ELOF1 modulates the response to transcription-blocking agents, and that the cytotoxicity of the G-quadruplex ligand pyridostatin involves trapping topoisomerase II on DNA. This map of the DNA damage response provides a rich resource to study this fundamental cellular system and has implications for the development and use of genotoxic agents in cancer therapy.
细胞对 DNA 损伤的反应对于细胞内稳态、肿瘤抑制、免疫和配子发生至关重要。为了提供人类细胞中 DNA 损伤反应的无偏和全面的视角，我们对视网膜色素上皮细胞-1（RPE1）细胞系中的 27 种遗传毒性药物进行了 31 次 CRISPR-Cas9 筛选。这些筛选确定了 890 个基因，这些基因的缺失导致对 DNA 损伤剂的敏感性或抗性。挖掘此数据集，我们发现 ERCC6L2（一种骨髓衰竭综合征中的突变基因）编码一个经典的非同源末端连接途径因子，RNA 聚合酶 II 成分 ELOF1 调节转录阻断剂的反应，以及 G-四链体配体吡啶司他汀的细胞毒性涉及拓扑异构酶 II 在 DNA 上的捕获。这个 DNA 损伤反应图谱为研究这个基本的细胞系统提供了丰富的资源，并对癌症治疗中遗传毒性药物的开发和使用具有重要意义。
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