NRDE2 deficiency impairs homologous recombination repair and sensitizes hepatocellular carcinoma to PARP inhibitors.

IF 11.1 Q1 CELL BIOLOGY Cell genomics Pub Date : 2024-05-08 Epub Date: 2024-05-01 DOI:10.1016/j.xgen.2024.100550
Yahui Wang, Xinyi Liu, Xianbo Zuo, Cuiling Wang, Zheng Zhang, Haitao Zhang, Tao Zeng, Shunqi Chen, Mengyu Liu, Hongxia Chen, Qingfeng Song, Qi Li, Chenning Yang, Yi Le, Jinliang Xing, Hongxin Zhang, Jiaze An, Weihua Jia, Longli Kang, Hongxing Zhang, Hui Xie, Jiazhou Ye, Tianzhun Wu, Fuchu He, Xuejun Zhang, Yuanfeng Li, Gangqiao Zhou
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Abstract

To identify novel susceptibility genes for hepatocellular carcinoma (HCC), we performed a rare-variant association study in Chinese populations consisting of 2,750 cases and 4,153 controls. We identified four HCC-associated genes, including NRDE2, RANBP17, RTEL1, and STEAP3. Using NRDE2 (index rs199890497 [p.N377I], p = 1.19 × 10-9) as an exemplary candidate, we demonstrated that it promotes homologous recombination (HR) repair and suppresses HCC. Mechanistically, NRDE2 binds to the subunits of casein kinase 2 (CK2) and facilitates the assembly and activity of the CK2 holoenzyme. This NRDE2-mediated enhancement of CK2 activity increases the phosphorylation of MDC1 and then facilitates the HR repair. These functions are eliminated almost completely by the NRDE2-p.N377I variant, which sensitizes the HCC cells to poly(ADP-ribose) polymerase (PARP) inhibitors, especially when combined with chemotherapy. Collectively, our findings highlight the relevance of the rare variants to genetic susceptibility to HCC, which would be helpful for the precise treatment of this malignancy.

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NRDE2 缺乏会损害同源重组修复,并使肝癌对 PARP 抑制剂敏感。
为了确定肝细胞癌(HCC)的新型易感基因,我们在中国人群中进行了一项罕见变异关联研究,其中包括 2,750 例病例和 4,153 例对照。我们发现了四个 HCC 相关基因,包括 NRDE2、RANBP17、RTEL1 和 STEAP3。我们以 NRDE2(指标 rs199890497 [p.N377I], p = 1.19 × 10-9)为例,证明它能促进同源重组(HR)修复并抑制 HCC。从机理上讲,NRDE2 与酪蛋白激酶 2(CK2)的亚基结合,促进了 CK2 全酶的组装和活性。NRDE2 介导的 CK2 活性增强会增加 MDC1 的磷酸化,进而促进 HR 修复。NRDE2-p.N377I变体几乎完全消除了这些功能,它使HCC细胞对多(ADP-核糖)聚合酶(PARP)抑制剂敏感,尤其是在与化疗联合使用时。总之,我们的研究结果凸显了罕见变异与 HCC 遗传易感性的相关性,这将有助于这种恶性肿瘤的精确治疗。
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