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

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 epitheliu...

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Detalles Bibliográficos
Autores: Olivieri, Michele, Cho, Tiffany, Álvarez-Quilón, Alejandro, Li, Kejiao, Schellenberg, Matthew J, Zimmermann, Michal, Hustedt, Nicole, Rossi, Silvia Emma, Adam, Salomé, 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
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/25358
Acceso en línea:https://hdl.handle.net/20.500.12105/25358
Access Level:acceso abierto
Palabra clave:CRISPR
DNA damage
DNA repair
DNA-damaging agents
cancer therapeutics
functional genomics
genome stability
mechanism-of-action
Descripción
Sumario: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.

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