Journal
CELL
Volume 182, Issue 2, Pages 481-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2020.05.040
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Funding
- EMBO fellowships [ALTF 910-2017, 795-2017, 124-2019]
- AIRC
- S.A.
- Asociacion Espanola Familia Ataxia Telangiectasia
- EMBO short-term fellowship
- Spanish Government (European Regional Development Fund) [SAF2017-89619-R]
- European Research Council [ERC-CoG-2014-647359]
- US National Institutes of Health Intramural Program, US National Institute of Environmental Health Sciences (NIEHS) [1Z01ES102765]
- CIHR [FDN143343, FRN 123518, PJT-156330]
- Canadian Cancer Society [705644]
- Krembil Foundation
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [ZIAES102765] Funding Source: NIH RePORTER
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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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