Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
Sci Adv. 2023 Oct 27;9(43):eadg7752. doi: 10.1126/sciadv.adg7752. Epub 2023 Oct 25.
Recent studies have pointed to PARP1 trapping as a key determinant of the anticancer effects of PARP1 inhibitors (PARPi). We identified RNF114, as a PARylation-dependent, E3 ubiquitin ligase involved in DNA damage response. Upon sensing genotoxicity, RNF114 was recruited, in a PAR-dependent manner, to DNA lesions, where it targeted PARP1 for degradation. The blockade of this pathway interfered with the removal of PARP1 from DNA lesions, leading to profound PARP1 trapping. We showed that a natural product, nimbolide, inhibited the E3 ligase activity of RNF114 and thus caused PARP1 trapping. However, unlike conventional PARPi, nimbolide treatment induced the trapping of both PARP1 and PARylation-dependent DNA repair factors. Nimbolide showed synthetic lethality with mutations, and it overcame intrinsic and acquired resistance to PARPi, both in vitro and in vivo. These results point to the exciting possibility of targeting the RNF114-PARP1 pathway for the treatment of homologous recombination-deficient cancers.
最近的研究表明，PARP1 捕获是 PARP1 抑制剂（PARPi）抗癌作用的关键决定因素。我们鉴定出 RNF114 是一种依赖 PAR 化的 E3 泛素连接酶，参与 DNA 损伤反应。在感知到遗传毒性后，RNF114 以 PAR 依赖性方式被招募到 DNA 损伤部位，在那里它将 PARP1 作为降解的靶标。阻断这条途径会干扰 PARP1 从 DNA 损伤部位的去除，导致 PARP1 大量捕获。我们表明，一种天然产物，尼姆波利德，抑制了 RNF114 的 E3 连接酶活性，从而导致 PARP1 捕获。然而，与传统的 PARPi 不同，尼姆波利德处理诱导了 PARP1 和 PAR 依赖性 DNA 修复因子的捕获。尼姆波利德在体外和体内均与 突变显示出合成致死性，并克服了对 PARPi 的内在和获得性耐药。这些结果表明，针对 RNF114-PARP1 途径治疗同源重组缺陷型癌症具有令人兴奋的可能性。
