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.

BRCA1或BRCA2肿瘤抑制基因的突变使个体易患乳腺癌和卵巢癌。在临床上，这些癌症采用针对聚（ADP-核糖）聚合酶（PARP）的抑制剂进行治疗。我们发现，抑制 DNPH1（一种消除细胞毒性核苷酸 5-羟甲基脱氧尿苷 (hmdU) 单磷酸盐的蛋白质）可增强BRCA缺陷细胞对 PARP 抑制剂 (PARPi) 的敏感性。合成致死性是由 SMUG1 糖基化酶对基因组 hmdU 的作用介导的，导致 PARP 捕获、复制叉塌陷、DNA 断裂形成和细胞凋亡。获得 PARPi 抗性的BRCA1缺陷细胞通过 hmdU 和 DNPH1 抑制处理重新敏感。由于基因组 hmdU 是 PARPi 敏感性的关键决定因素，因此靶向 DNPH1 为BRCA缺陷型癌症对 PARPi 治疗的超敏化提供了一种有前景的策略。