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- Title
Genome-scale CRISPR knockout screen identifies TIGAR as a modifier of PARP inhibitor sensitivity.
- Authors
Fang, Pingping; De Souza, Cristabelle; Minn, Kay; Chien, Jeremy
- 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. Pingping Fang et al. report a CRISPR/Cas9-based genome-scale loss-of-function screen identifying TIGAR as a modifier of response to PARP inhibition. The authors find that knockdown of TIGAR increases intracellular reactive oxygen species levels, enhances more DNA damage after olaparib treatment, and induces a state of "BRCAness", suggesting that TIGAR is a potential therapeutic target in ovarian cancer patients.
- Subjects
GENOMES; CRISPRS; CANCER treatment; ADENOSINE diphosphate ribose; DOWNREGULATION; CELL-mediated cytotoxicity
- Publication
Communications Biology, 2019, Vol 2, Issue 1, pN.PAG
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-019-0580-6