Genome-scale CRISPR knockout screen identifies TIGAR as a modifier of PARP inhibitor sensitivity

Pingping Fang, Cristabelle De Souza, Kay Minn, Jeremy Chien

Research output: Contribution to journalArticle

Abstract

Treatment of cancer with poly (ADP-ribose) polymerase (PARP) inhibitors is currently limited to cells defective in the homologous recombination (HR) pathway. Identification of genetic targets that induce or mimic HR deficiencies will extend the clinical utility of PARP inhibitors. Here we perform a CRISPR/Cas9-based genome-scale loss-of-function screen, using the sensitivity of PARP inhibitor olaparib as a surrogate. We identify C12orf5, encoding TP53 induced glycolysis and apoptosis regulator (TIGAR), as a modifier of PARP inhibitor response. We show that TIGAR is amplified in several cancer types, and higher expression of TIGAR associates with poor overall survival in ovarian cancer. TIGAR knockdown enhances sensitivity to olaparib in cancer cells via downregulation of BRCA1 and the Fanconi anemia pathway and increases senescence of these cells by affecting metabolic pathways and increasing the cytotoxic effects of olaparib. Our results indicate TIGAR should be explored as a therapeutic target for treating cancer and extending the use of PARP inhibitors.

Original languageEnglish (US)
Article number335
JournalCommunications Biology
Volume2
Issue number1
DOIs
StatePublished - Dec 1 2019

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Clustered Regularly Interspaced Short Palindromic Repeats
NAD ADP-ribosyltransferase
modifiers (genes)
glycolysis
Glycolysis
apoptosis
Genes
Genome
Apoptosis
genome
Homologous Recombination
homologous recombination
neoplasms
Neoplasms
Fanconi Anemia
ovarian neoplasms
Cell Aging
Metabolic Networks and Pathways
Ovarian Neoplasms
biochemical pathways

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Medicine (miscellaneous)

Cite this

Genome-scale CRISPR knockout screen identifies TIGAR as a modifier of PARP inhibitor sensitivity. / Fang, Pingping; De Souza, Cristabelle; Minn, Kay; Chien, Jeremy.

In: Communications Biology, Vol. 2, No. 1, 335, 01.12.2019.

Research output: Contribution to journalArticle

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