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

• DOI: 10.1016/j.xgen.2024.100550
• Publication Date: 2024-05-01T14:48:39Z
• Authors: 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
• Keywords: Male; Carcinoma, Hepatocellular; Liver Neoplasms; Recombinational DNA Repair; Poly(ADP-ribose) Polymerase Inhibitors; Middle Aged; Article; Mice; Cell Line, Tumor; Humans; Animals; Female; Genetic Predisposition to Disease; Casein Kinase II

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, STEAP3. Using NRDE2 (index rs199890497 [p.N377I], p = 1.19 × 10−9) as an exemplary candidate, demonstrated that it promotes homologous recombination (HR) repair suppresses HCC. Mechanistically, binds to the subunits casein kinase 2 (CK2) facilitates assembly activity CK2 holoenzyme. This NRDE2-mediated enhancement increases phosphorylation MDC1 then HR repair. These functions are eliminated almost completely by NRDE2-p.N377I variant, which sensitizes HCC cells poly(ADP-ribose) polymerase (PARP) inhibitors, especially when combined with chemotherapy. Collectively, our findings highlight relevance rare variants genetic HCC, would be helpful precise treatment this malignancy.