人类细胞响应DNA损伤的遗传图谱

为了ti供人类细胞中DNA损伤响应的无偏和全局观测，研究对视网膜色素上皮1（RPE1）细胞系中的27种遗传毒性剂进行了31次CRISPR-Cas9筛选。这些筛选确定了890个基因，这些基因的丢失导致对DNA破坏剂的敏感性或抗性。

 通过挖掘此数据集，研究发现ERCC6L2（这在gu髓衰竭综合征中发生突变）编码经典的非同源末端连接途径因子，以及RNA聚合酶II成分ELOF1调节对转录阻断剂的反应，此外 G-四链体配体pyridostatin的细胞毒性与拓扑异构酶II在DNA上的阻碍相关。

 这种DNA损伤反应图谱为研究这一基本细胞系统ti供了丰富的资源，并且对遗传疗法在癌症治疗中的开发和使用具有重要意义。

 DNA损伤反应对于细胞动态平衡、肿瘤抑制、免疫力和配子形成至关重要。

附：英文原文

Title: A Genetic Map of the Response to DNA Damage in Human Cells

Author: Michele Olivieri, Tiffany Cho, Alejandro álvarez-Quilón, Kejiao Li, Matthew J. Schellenberg, Michal Zimmermann, Nicole Hustedt, Silvia Emma Rossi, Salomé Adam, Henrique Melo, Anne Margriet Heijink, Guillermo Sastre-Moreno, Nathalie Moatti, Rachel K. Szilard, Andrea McEwan, Alexanda K. Ling, Almudena Serrano-Benitez, Tajinder Ubhi, Sumin Feng, Judy Pawling, Irene Delgado-Sainz, Michael W. Ferguson, James W. Dennis, Grant W. Brown, Felipe Cortés-Ledesma, R. Scott Williams, Alberto Martin, Dongyi Xu, Daniel Durocher

Issue&Volume: 2020-07-09

Abstract: 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.

DOI: 10.1016/j.cell.2020.05.040

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30673-5