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

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dc.contributor.authorOlivieri, Michele
dc.contributor.authorCho, Tiffany
dc.contributor.authorÁlvarez-Quilón, Alejandro
dc.contributor.authorLi, Kejiao
dc.contributor.authorSchellenberg, Matthew J
dc.contributor.authorZimmermann, Michal
dc.contributor.authorHustedt, Nicole
dc.contributor.authorRossi, Silvia Emma
dc.contributor.authorAdam, Salomé
dc.contributor.authorMelo, Henrique
dc.contributor.authorHeijink, Anne Margriet
dc.contributor.authorSastre-Moreno, Guillermo
dc.contributor.authorMoatti, Nathalie
dc.contributor.authorSzilard, Rachel K
dc.contributor.authorMcEwan, Andrea
dc.contributor.authorLing, Alexanda K
dc.contributor.authorSerrano-Benitez, Almudena
dc.contributor.authorUbhi, Tajinder
dc.contributor.authorFeng, Sumin
dc.contributor.authorPawling, Judy
dc.contributor.authorDelgado-Sainz, Irene
dc.contributor.authorFerguson, Michael W
dc.contributor.authorDennis, James W
dc.contributor.authorBrown, Grant W
dc.contributor.authorCortes-Ledesma, Felipe
dc.contributor.authorWilliams, R Scott
dc.contributor.authorMartin, Alberto
dc.contributor.authorXu, Dongyi
dc.contributor.authorDurocher, Daniel
dc.contributor.authorOlivieri, Michele
dc.contributor.authorCho, Tiffany
dc.contributor.authorÁlvarez-Quilón, Alejandro
dc.contributor.authorLi, Kejiao
dc.contributor.authorSchellenberg, Matthew J
dc.contributor.authorZimmermann, Michal
dc.contributor.authorHustedt, Nicole
dc.contributor.authorRossi, Silvia Emma
dc.contributor.authorAdam, Salomé
dc.contributor.authorMelo, Henrique
dc.contributor.authorHeijink, Anne Margriet
dc.contributor.authorSastre-Moreno, Guillermo
dc.contributor.authorMoatti, Nathalie
dc.contributor.authorSzilard, Rachel K
dc.contributor.authorMcEwan, Andrea
dc.contributor.authorLing, Alexanda K
dc.contributor.authorSerrano-Benitez, Almudena
dc.contributor.authorUbhi, Tajinder
dc.contributor.authorFeng, Sumin
dc.contributor.authorPawling, Judy
dc.contributor.authorDelgado-Sainz, Irene
dc.contributor.authorFerguson, Michael W
dc.contributor.authorDennis, James W
dc.contributor.authorBrown, Grant W
dc.contributor.authorWilliams, R Scott
dc.contributor.authorMartin, Alberto
dc.contributor.authorXu, Dongyi
dc.contributor.authorDurocher, Daniel
dc.contributor.funderEMBO
dc.contributor.funderUnión Europea. Comisión Europea. European Research Council (ERC)
dc.contributor.funderUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
dc.contributor.funderCanadian Institutes of Health Research (CIHR)
dc.contributor.funderCanadian Cancer Society (CCS)
dc.contributor.funderKrembil Foundation
dc.date.accessioned2024-10-29T08:45:23Z
dc.date.available2024-10-29T08:45:23Z
dc.date.issued2020-07-23
dc.descriptionWe thank J.Y. Yuan for technical assistance as well as J. Moffat, S. Angers, and T. Hart for the TKO libraries and protocols and C. Boone for yeast strains. We also thank F. Meng, S. Rottenberg, and M. Luijsterburg for sharing unpublished results. A.A.Q., G.S.M., and A.M.H. are recipients of long-term EMBO fellowships (ALTF 910-2017, 795-2017, and 124-2019), S.E.R. was supported by a fellowship from AIRC, and S.A. was a Banting post-doctoral fellow. A.S.B. was supported by a PhD Studentship from Asociacion Espanola Familia Ataxia Telangiectasia and an EMBO short-term fellowship. The ICRF-187 was funded by the Spanish Government (SAF2017-89619-R, European Regional Development Fund) and European Research Council (ERC-CoG-2014-647359). Work in the R.S.W. laboratory was supported in part by the US National Institutes of Health Intramural Program, US National Institute of Environmental Health Sciences (NIEHS, 1Z01ES102765). D.D. is a Canada Research Chair (Tier I), and the work was supported by grants from the CIHR (FDN143343 to D.D.; FRN 123518 and PJT-156330 to A.Martin) and Canadian Cancer Society grant (705644 to D.D.) with additional support to D.D. from the Krembil Foundation.
dc.description.abstractThe 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.
dc.description.peerreviewedSí
dc.format.number2
dc.format.page481-496
dc.format.volume182
dc.identifier.citationCell . 2020 Jul 23;182(2):481-496.e21.
dc.identifier.journalCell
dc.identifier.pmchttps://pmc.ncbi.nlm.nih.gov/articles/PMC7384976/pdf/nihms-1598385.pdf
dc.identifier.pubmedID32649862
dc.identifier.urihttps://hdl.handle.net/20.500.12105/25358
dc.language.isoeng
dc.publisherCell Press
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-89619-R/ES/PAPEL DE LA TOPOISOMERASA II EN LA ORGANIZACION, EXPRESION Y ESTABILIDAD DEL GENOMA: IMPLICACIONES PATOLOGICAS Y OPORTUNIDADES TERAPEUTICAS/
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/H2020/647359/EU
dc.relation.publisherversionhttp://www.10.1016/j.cell.2020.05.040
dc.repisalud.institucionCNIO
dc.rights.accessRightsopen access
dc.rights.licenseAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectCRISPR
dc.subjectDNA damage
dc.subjectDNA repair
dc.subjectDNA-damaging agents
dc.subjectcancer therapeutics
dc.subjectfunctional genomics
dc.subjectgenome stability
dc.subjectmechanism-of-action
dc.titleA Genetic Map of the Response to DNA Damage in Human Cells.
dc.typeresearch article
dc.type.hasVersionVoR
dspace.entity.typePublication
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