Targeting the nucleotide salvage factor DNPH1 sensitizes BRCA-deficient cells to PARP inhibitors.
Targeting the nucleotide salvage factor DNPH1 sensitizes BRCA-deficient cells to PARP inhibitors.
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DOI：
10.1126/science.abb4542
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发表时间：
2021-04-09
期刊：
影响因子：
--
通讯作者：
West SC
中科院分区：
文献类型：
--
作者：
Fugger K;Bajrami I;Silva Dos Santos M;Young SJ;Kunzelmann S;Kelly G;Hewitt G;Patel H;Goldstone R;Carell T;Boulton SJ;MacRae J;Taylor IA;West SC
BRCA 1或BRCA 2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，这些癌症用靶向聚[ADP-核糖]聚合酶（PARP）的抑制剂治疗。我们发现，DNPH 1，一种消除细胞毒性核苷酸羟甲基脱氧尿苷（hmdU）单磷酸的蛋白质，抑制增强BRCA缺陷细胞对PARP抑制剂（PARPi）的敏感性。SMUG 1糖基化酶对基因组hmdU的作用介导了合成致死，导致PARP捕获、复制叉崩溃、DNA断裂形成和凋亡。通过用hmdU和DNPH 1抑制剂处理获得对PARPi的抗性的BRCA 1缺陷细胞而重新致敏。由于基因组hmdU是PARPi敏感性的关键决定因素，因此靶向DNPH 1为BRCA缺陷型癌症对PARPi治疗的超敏反应提供了一种有希望的策略。
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 the cytotoxic nucleotide 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 re-sensitized 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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