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

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

Publicación: CELL
2020
VL / 182 - BP / 481 - EP / +
abstract
The response to DNA damage is critical for cellular homeostasis, tumor suppression, immunity, and game-togenesis. 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.

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