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Cited by 551DNA Repair MechanismsCRISPR and Genetic EngineeringCarcinogens and Genotoxicity Assessment

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

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Olivieri, Michele, Cho, Tiffany, Álvarez-Quilón, Alejandro, Li, Kejiao, Schellenberg, Matthew J., Zimmermann, Michal, Hustedt, Nicole, Rossi, Silvia Emma +21 more·2020·Cell
DOI 10.1016/j.cell.2020.05.040PMC PMC7384976

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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.

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  • Many genes identified from iCRISPRi pooled screens in 3D human gastric organoids were not determined as cisplatin sensitization partners in previous genome-scale CRISPR KO screens in immortalized 2D human cell lines.

    “In particular, many genes identified from our iCRISPRi pooled screens in 3D human gastric organoids were not determined as cisplatin sensitization partners in previous genome-scale CRISPR KO screens in immortalized 2D human cell lines51, suggesting potential 3D specificity (Fig. S6A).”

    From Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions (2025) · cites this paper as [51]

  • Recent genome-wide investigations underscore that these effects are not confined to promotors, but are rather observed across the genome.

    “Recent genome-wide investigations underscore that these effects are not confined to promotors, but are rather observed across the genome (68–70).”

    From G-quadruplex-mediated genomic instability drives SNVs in cancer (2024) · cites this paper as [69]

    The Results (‘Global view of the screens’; page unavailable) describe genome-wide screens for genes affecting the response to DNA damage. Our copy does not say that the effects invoked by the citing sentence occur outside promoters or across genomic locations; a search for promoters and genomic distribution found no such passage. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

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Authors
Olivieri, M., Cho, T., Álvarez-Quilón, A., Li, K., Schellenberg, M. J., Zimmermann, M., Hustedt, N., Rossi, S. E., Adam, S., Melo, H., Heijink, A. M., Sastre-Moreno, G., Moatti, N., Szilard, R. K., McEwan, A., Ling, A. K., Serrano-Benitez, A., Ubhi, T., Feng, S., Pawling, J., Delgado-Sainz, I., Ferguson, M. W., Dennis, J. W., Brown, G. W., Cortés-Ledesma, F., Williams, R. S., Martin, A., Xu, D., & Durocher, D.
Affiliations
  • Mount Sinai Hospital (CA)
  • Peking University (CN)
  • National Institutes of Health (US)
  • University of Toronto (CA)
Corresponding author
Durocher, Daniel
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2020-07
Volume
182
Issue
2
Pages
481-496.e21
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2020.05.040
PMC
PMC7384976
OpenAlex
W3042118153
Cited by
551
References
13
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23.93
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journal article
Language
en
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  • Cell (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RISalud Institutional Health Repository of Andalucía (submittedVersion, other-oa)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by-nc-nd)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
Funders
  • European Research Council
  • EMBO
  • National Institute of Environmental Health Sciences
  • Canadian Institutes of Health Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
Keywords
DNA damage response, CRISPR-Cas9 screen, RPE1 cells, DNA-damaging agents, non-homologous end joining, pyridostatin, G-quadruplex ligands, topoisomerase II, bone marrow failure syndromes, cancer therapy, drug sensitivity and resistance
MeSH terms
RNA, Guide, CRISPR-Cas Systems, Aminoquinolines, Animals, Cell Line, DNA Damage, DNA Topoisomerases, Type II, DNA Repair, DNA Helicases, Humans, Picolinic Acids, Tumor Suppressor Protein p53, RNA, Guide, Kinetoplastida, Cytochrome-B(5) Reductase, Mice, Gene Regulatory Networks, CRISPR-Cas Systems

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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