NRDE2 deficiency impairs homologous recombination repair and sensitizes hepatocellular carcinoma to PARP inhibitors
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, Wei‐Hua Jia, Longli Kang, Hong‐Xing Zhang, Hui Xie, Jiazhou Ye, Tianzhun Wu, Fuchu He, Xuejun Zhang, Yuanfeng Li, Gangqiao Zhou
Abstract
) 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.