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

Michele Olivieri, Tiffany Cho, Alejandro Álvarez-Quilón, Kejiao Li, Matthew J. Schellenberg, Michal Zimmermann, Nicole Hustedt, Silvia Emma Rossi, Salomé Adam, Henrique Melo, Anne Margriet Heijink, Guillermo Sastre-Moreno, Nathalie Moatti, Rachel K. Szilard, Andrea McEwan, Alexanda K. Ling, Almudena Serrano-Benitez, Tajinder Ubhi, Sumin Feng, Judy PawlingIrene Delgado-Sainz, Michael W. Ferguson, James W. Dennis, Grant W. Brown, Felipe Cortés-Ledesma, R. Scott Williams, Alberto Martin, Dongyi Xu, Daniel Durocher

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)481-496.e21
JournalCell
Volume182
Issue number2
DOIs
StatePublished - Jul 23 2020

Keywords

  • CRISPR
  • DNA damage
  • DNA repair
  • DNA-damaging agents
  • cancer therapeutics
  • functional genomics
  • genome stability
  • mechanism-of-action

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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