Three strikes to eliminate cancer
BRCA1 and BRCA2 are tumor-suppressing genes, and patients with mutations in these genes are prone to breast cancer, ovaries and other cancers. Because BRCA1 and BRCA2 mutations affect pathways involved in DNA disruption repair, the tumors of these patients are usually vulnerable to treatments that further damage DNA repair, such as poly (ADP-ribose) polymerase (PARP) inhibitors, but they may be resistant to get therapy. Using a Genome-wide screening approach, Fugger et al. has identified a protein called DNPH1 as a ‘nucleotide purifier’ that prevents the incorporation of abnormal nucleotides into DNA (see the Perspective by Kriaucionis). The authors examined its mechanism of action and showed how it could be targeted to kill BRCA1mutant cancer cells in combination with PARP inhibitor treatment.
Science, this issue p. 156; see also p. 127
Summary
Mutations in the BRCA1 or BRCA2 tumor suppressor genes predispose individuals to breast cancer 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, reduces the sensitivity of BRCAdeficiency of PARP inhibitors (PARPi). Synthetic lethality was mediated by the action of SMUG1 glycosylase on genomic hmdU, leading to PARP capture, replication fork collapse, DNA breakage, and apoptosis. BRCA1deficient cells that developed resistance to PARPi were resensitized by treatment with hmdU and DNPH1 inhibition. Because genomic hmdU is an important determinant of PARPi sensitivity, the focus on DNPH1 offers a promising strategy for the hypersensitivity of BRCAcancer deficiencies for PARPi therapy.