1. A Genetic Map of the Response to DNA Damage in Human Cells
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Andrea McEwan, Silvia Emma Rossi, Daniel Durocher, Felipe Cortés-Ledesma, Michal Zimmermann, Nathalie Moatti, Henrique Melo, Guillermo Sastre-Moreno, James W. Dennis, Alexanda K. Ling, Judy Pawling, Anne Margriet Heijink, Michele Olivieri, Sumin Feng, Nicole Hustedt, Irene Delgado-Sainz, R. Scott Williams, Michael W. Ferguson, Matthew J. Schellenberg, Alberto Martin, Almudena Serrano-Benitez, Grant W. Brown, Kejiao Li, Dongyi Xu, Tiffany Cho, Alejandro Álvarez-Quilón, Salomé Adam, Tajinder Ubhi, Rachel K. Szilard, EMBO, Human Frontier Science Program, Associazione Italiana per la Ricerca sul Cancro, Asociación Española Familia Ataxia Telangiectasia, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, European Research Council, National Institutes of Health (US), National Institute of Environmental Health Sciences (US), Canada Research Chairs, Canadian Institutes of Health Research, Canadian Cancer Society, Krembil Foundation, Olivieri, Michele [0000-0002-0257-998X], Cho, Tiffany [0000-0001-7223-2394], Álvarez-Quilón, Alejandro [0000-0001-9330-6823], Schellenberg, Matthew J. [0000-0001-7036-5943], Hustedt, Nicole [0000-0002-7529-5769], Rossi, Silvia Emma [0000-0001-9950-3860], Heijink, Anne Margriet [0000-0001-9229-0575], Sastre-Moreno, Guillermo [0000-0001-7535-555X], Moatti, Nathalie [0000-0002-4703-2371], Ling, Alexandra K. [0000-0002-1687-2554], Ubhi, Tajinder [0000-0002-9107-1888], Ferguson, Michael W. [0000-0001-5163-9689], Brown, Grant W. [0000-0002-9002-5003], Cortés-Ledesma, Felipe [0000-0002-0440-6783], Williams, R. Scott [0000-0002-4610-8397], Martin, Alberto [0000-0002-0795-0418], Xu, Dongyi [0000-0001-5711-2618], Durocher, Daniel [0000-0003-3863-8635], Olivieri, Michele, Cho, Tiffany, Álvarez-Quilón, Alejandro, Schellenberg, Matthew J., Hustedt, Nicole, Rossi, Silvia Emma, Heijink, Anne Margriet, Sastre-Moreno, Guillermo, Moatti, Nathalie, Ling, Alexandra K., Ubhi, Tajinder, Ferguson, Michael W., Brown, Grant W., Cortés-Ledesma, Felipe, Williams, R. Scott, Martin, Alberto, Xu, Dongyi, and Durocher, Daniel
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DNA Repair ,DNA repair ,DNA damage ,education ,Cellular homeostasis ,RNA polymerase II ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,cancer therapeutics ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Genome stability ,Animals ,Humans ,CRISPR ,Gene Regulatory Networks ,Picolinic Acids ,Gene ,Mechanism-of-action ,030304 developmental biology ,0303 health sciences ,biology ,Cas9 ,Topoisomerase ,DNA Helicases ,Functional genomics ,3. Good health ,Cell biology ,DNA Topoisomerases, Type II ,mechanism-of-action ,chemistry ,Aminoquinolines ,biology.protein ,CRISPR-Cas Systems ,Tumor Suppressor Protein p53 ,Cancer therapeutics ,DNA-damaging agents ,Homologous recombination ,functional genomics ,genome stability ,Cytochrome-B(5) Reductase ,030217 neurology & neurosurgery ,DNA ,RNA, Guide, Kinetoplastida - Abstract
Versión postprint próximamente disponible en: http://hdl.handle.net/10261/228202, 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 28 CRISPR/Cas9 screens against 25 genotoxic agents in the retinal pigment epithelium-1 (RPE1) cell line. These screens identified 840 genes whose loss causes either sensitivity or resistance to DNA damaging agents. Mining this dataset, we uncovered 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., AAQ, GSM and AMH are recipients of long-term EMBO fellowships (ALTF 910-2017, 795-2017 under a CC-BY-NC-ND 4.0 International license. not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available bioRxiv preprint doi: https://doi.org/10.1101/845446; this version posted November 18, 2019. The copyright holder for this preprint (which was 27 and 124-2019, respectively), NH was supported by a Human Frontier Science Program long-term Fellowship, SER is supported by a fellowship from AIRC and SA was a Banting post-doctoral fellow. ASB was supported by a PhD Studentship from AEFAT (Asociación Española Familia Ataxia Telangiectasia) and an EMBO short-term fellowship for a visit to the DD laboratory. The ICRF187 screen in FCL laboratory was funded by grants from the Spanish Government (SAF2017- 89619-R, European Regional Development Fund) and the European Research Council (ERC-CoG2014-647359). Work in the RSW laboratory was supported in part by the US National Institute of Health Intramural Program, US National Institute of Environmental Health Sciences (NIEHS, 1Z01ES102765). DD is a Canada Research Chair (Tier I) and the work was supported from grants from the CIHR (FDN143343 to DD; FRN 123518, PJT-156330 to AM) Canadian Cancer Society grant 705644 (to DD) with additional support to DD from the Krembil Foundation.
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