Research Article

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

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Science  09 Apr 2021:
Vol. 372, Issue 6538, pp. 156-165
DOI: 10.1126/science.abb4542

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Three strikes to knock cancer out

BRCA1 and BRCA2 are tumor-suppressor genes, and patients with mutations in these genes are predisposed to breast, ovarian, and other cancers. Because BRCA1 and BRCA2 mutations affect pathways involved in DNA break repair, these patients' tumors are usually vulnerable to treatments that further damage DNA repair, such as poly(ADP-ribose) polymerase (PARP) inhibitors, but they can acquire resistance to therapy. Using a genome-wide screening approach, Fugger et al. identified a protein called DNPH1 as a “nucleotide sanitizer” that prevents the incorporation of abnormal nucleotides into DNA (see the Perspective by Kriaucionis). The authors examined its mechanism of action and demonstrated how it can be targeted to expedite the killing of BRCA1-mutant cancer cells in combination with PARP inhibitor treatment.

Science, this issue p. 156; see also p. 127

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.

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