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

NRDE2 缺乏损害同源重组修复并使肝细胞癌对 PARP 抑制剂敏感。

• 发表时间: 2024 May 8
• 来源期刊: Cell Genom
• DOI: 10.1016/j.xgen.2024.100550
• PMID: 38697125
• 文章类型: Journal Article
• 作者列表: Wang Y,Liu X,Zuo X,Wang C,Zhang Z,Zhang H,Zeng T,Chen S,Liu M,Chen H,Song Q,Li Q,Yang C,Le Y,Xing J,Zhang H,An J,Jia W,Kang L,Zhang H,Xie H,Ye J,Wu T,He F,Zhang X,Li Y,Zhou G

关键词: NRDE2; PARP inhibitors; hepatocellular carcinoma; homologous recombination repair; rare variant

Mesh: Animals; Female; Humans; Male; Mice; Middle Aged; Carcinoma, Hepatocellular / drug therapy genetics pathology; Casein Kinase II / genetics metabolism; Cell Line, Tumor; Genetic Predisposition to Disease; Liver Neoplasms / drug therapy genetics pathology; Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use pharmacology; Recombinational DNA Repair / drug effects; Mice, Nude; Mice, Inbred BALB C; Adult

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.

摘要

鉴定肝细胞癌（HCC）的新易感基因，我们在由2,750例病例和4,153例对照组成的中国人群中进行了罕见变异关联研究.我们确定了四个HCC相关基因，包括NRDE2、RANBP17、RTEL1和STEAP3。使用NRDE2(索引rs199890497[p。N377I],p=1.19×10-9)作为示例性候选，我们证明它促进同源重组（HR）修复并抑制HCC。机械上,NRDE2与酪蛋白激酶2（CK2）的亚基结合，并促进CK2全酶的组装和活性。这种NRDE2介导的CK2活性增强增加了MDC1的磷酸化，然后促进了HR修复。NRDE2-p几乎完全消除了这些功能。N377I变体,使肝癌细胞对聚（ADP-核糖）聚合酶（PARP）抑制剂敏感，尤其是联合化疗时。总的来说，我们的发现强调了罕见变异与肝癌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。