| Literature DB >> 32649862 |
Michele Olivieri1, Tiffany Cho1, Alejandro Álvarez-Quilón2, Kejiao Li3, Matthew J Schellenberg4, Michal Zimmermann2, Nicole Hustedt2, Silvia Emma Rossi2, Salomé Adam2, Henrique Melo2, Anne Margriet Heijink2, Guillermo Sastre-Moreno2, Nathalie Moatti2, Rachel K Szilard2, Andrea McEwan2, Alexanda K Ling5, Almudena Serrano-Benitez6, Tajinder Ubhi7, Sumin Feng2, Judy Pawling2, Irene Delgado-Sainz6, Michael W Ferguson7, James W Dennis1, Grant W Brown7, Felipe Cortés-Ledesma6, R Scott Williams4, Alberto Martin5, Dongyi Xu3, Daniel Durocher8.
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.Entities:
Keywords: CRISPR; DNA damage; DNA repair; DNA-damaging agents; cancer therapeutics; functional genomics; genome stability; mechanism-of-action
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Year: 2020 PMID： 32649862 PMCID： PMC7384976 DOI： 10.1016/j.cell.2020.05.040
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582