Targeting the nucleotide salvage factor DNPH1 sensitizes BRCA-deficient cells to PARP inhibitors

Kasper Fugger, Ilirjana Bajrami, Mariana Silva Dos Santos, Sarah Jane Young, Simone Kunzelmann, Geoff Kelly, Graeme Hewitt, Harshil Patel, Robert Goldstone, Thomas Carell, Simon J. Boulton, James MacRae, Ian A. Taylor, Stephen C. West

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)156-165
Number of pages10
JournalScience
Volume372
Issue number6538
DOIs
StatePublished - 9 Apr 2021
Externally publishedYes

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