Targeting the nucleotide salvage factor DNPH1 sensitizes BRCA-deficient cells to PARP inhibitors
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Kasper Fugger Ilirjana Bajrami Mariana Silva Dos Santos Sarah Young Simone Kunzelmann Geoff Kelly Graeme Hewitt Harshil Patel Robert Goldstone Thomas Carell Simon Boulton James Macrae Ian Taylor Stephen WestAbstract
Mutations in the BRCA1 or BRCA2 tumor suppressor genes predispose individuals to breast and ovarian cancer. In the clinic, these cancers are treated with inhibitors that target poly(ADP-ribose) polymerase (PARP). We show that inhibition of DNPH1, a protein that eliminates cytotoxic nucleotide 5-hydroxymethyl-deoxyuridine (hmdU) monophosphate, potentiates the sensitivity of BRCA-deficient cells to PARP inhibitors (PARPi). Synthetic lethality was mediated by the action of SMUG1 glycosylase on genomic hmdU, leading to PARP trapping, replication fork collapse, DNA break formation, and apoptosis. BRCA1-deficient cells that acquired resistance to PARPi were resensitized by treatment with hmdU and DNPH1 inhibition. Because genomic hmdU is a key determinant of PARPi sensitivity, targeting DNPH1 provides a promising strategy for the hypersensitization of BRCA-deficient cancers to PARPi therapy.
Journal details
Journal Science
Volume 372
Issue number 6538
Pages 156-165
Available online
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Publisher website (DOI) 10.1126/science.abb4542
Europe PubMed Central 33833118
Pubmed 33833118
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