NADP+ is an endogenous PARP inhibitor in DNA damage response and tumor suppression
NADP+ is an endogenous PARP inhibitor in DNA damage response and tumor suppression
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NADP( ) 是一种内源性 PARP 抑制剂，用于 DNA 损伤反应和肿瘤抑制
DOI：
10.1038/s41467-019-08530-5
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发表时间：
2019-02-11
影响因子：
16.6
通讯作者：
Yu, Xiaochun
中科院分区：
文献类型：
--
作者：
Bian, Chunjing;Zhang, Chao;Yu, Xiaochun
ADP-核糖基化是聚ADP-核糖聚合酶（PARP）以NAD（+）为ADP-核糖供体催化的独特的翻译后修饰。PARP在DNA损伤修复中起着不可或缺的作用，小分子PARP抑制剂已成为有效的抗癌药物。然而，迄今为止，PARP抑制剂治疗仅限于BRCA 1/2突变相关的乳腺癌和卵巢癌患者。将PARP抑制剂的治疗潜力扩展到其他癌症类型的主要挑战之一是缺乏预测性生物标志物。在这里，我们发现卵巢癌细胞具有较高水平的NADP（+），一种NAD（+）衍生物，对PARP抑制剂更敏感。我们证明，NADP（+）作为一个负调节和抑制ADP-核糖基化在体外和体内。NADP（+）破坏ADP核糖基化依赖的DNA损伤修复，并使肿瘤细胞对化学合成的PARP抑制剂敏感。总之，我们的研究确定NADP（+）作为一种内源性PARP抑制剂，可能对癌症治疗有影响。
ADP-ribosylation is a unique posttranslational modification catalyzed by poly(ADP-ribose) polymerases (PARPs) using NAD(+) as ADP-ribose donor. PARPs play an indispensable role in DNA damage repair and small molecule PARP inhibitors have emerged as potent anticancer drugs. However, to date, PARP inhibitor treatment has been restricted to patients with BRCA1/2 mutation-associated breast and ovarian cancer. One of the major challenges to extend the therapeutic potential of PARP inhibitors to other cancer types is the absence of predictive biomarkers. Here, we show that ovarian cancer cells with higher level of NADP(+), an NAD(+) derivative, are more sensitive to PARP inhibitors. We demonstrate that NADP(+) acts as a negative regulator and suppresses ADP-ribosylation both in vitro and in vivo. NADP(+) impairs ADP-ribosylation-dependent DNA damage repair and sensitizes tumor cell to chemically synthesized PARP inhibitors. Taken together, our study identifies NADP(+) as an endogenous PARP inhibitor that may have implications in cancer treatment.