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

Abstract

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