Scientific Advances: Potentiating PARP inhibitors in BRCA1 and 2 deficient tumor cells

From the lab of Stephen West, a genome-wide CRISPR screen to dissect cellular sensitivity and resistance to PARP-inhibitors (PARPi) was recently published in Science. Using the Brunello genome-wide sgRNA library and cells deficient in the endonuclease MUS81, the authors identified that sensitivity to PARPi can be increased by preventing nucleotide pool polishing through DNPH1, which eliminates cytotoxic nucleotide 5-hydroxymethyl-deoxyuridine (hmdU) monophosphate. In addition, it was reported that synthetic lethality mediated by PARPi and loss of BRCA is fully dependent on the function of the glycosylase SMUG1.

For more information, see: Fugger, K., et al. (2021) Targeting the nucleotide salvage factor DNPH1 sensitizes BRCA-deficient cells to PARP inhibitors. Science 372: 156-165. DOI: 10.1126/science.abb4542

Keywords: CRISPR screen, PARP inhibitor, BRCA

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