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

Autor: 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
Přispěvatelé: 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, Durocher, Daniel
Jazyk: angličtina
Předmět:
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
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
instname
ISSN: 0092-8674
DOI: 10.1016/j.cell.2020.05.040
Popis: 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.
Databáze: OpenAIRE
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