英国弗朗西斯-克里克研究所Stephen C. West、Kasper Fugger等研究人员合作发现，靶向DNPH1能够使BRCA缺陷细胞对PARP抑制剂敏感。相关论文于2021年4月9日发表在《科学》杂志上。

研究人员发现，抑制DNPH1，一种消除细胞毒性核苷酸5-羟甲基-脱氧尿苷（hmdU）单磷酸的蛋白质，可增强BRCA缺陷细胞对聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPi）的敏感性。合成致死是由SMUG1糖基化酶对基因组hmdU的作用介导的，导致PARP卡死、复制叉塌陷、DNA断裂形成和凋亡。

hmdU和DNPH1抑制处理能够使获得PARPi抗性的BRCA1缺陷细胞重新敏感。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途的策略。

据悉，BRCA1或BRCA2肿瘤抑制基因的突变使个体容易患乳腺癌和卵巢癌。在临床中，这些癌症用靶向聚（ADP-核糖）聚合酶（PARP）的抑制剂治疗。

附：英文原文

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

Author: Kasper Fugger, Ilirjana Bajrami, Mariana Silva Dos Santos, Sarah Jane Young, Simone Kunzelmann, Geoff Kelly, Graeme Hewitt, Harshil Patel, Robert Goldstone, Thomas Carell, Simon J. Boulton, James MacRae, Ian A. Taylor, Stephen C. West

Issue&Volume: 2021/04/09

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.

DOI: 10.1126/science.abb4542

Source: https://science.sciencemag.org/content/372/6538/156