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

被引：3

作者：

Wang, Yahui ^{[1
,2
]}

Liu, Xinyi ^{[1
]}

Zuo, Xianbo ^{[3
]}

Wang, Cuiling ^{[1
]}

Zhang, Zheng ^{[1
]}

Zhang, Haitao ^{[1
]}

Zeng, Tao ^{[4
]}

Chen, Shunqi ^{[1
]}

Liu, Mengyu ^{[1
]}

Chen, Hongxia ^{[1
]}

Song, Qingfeng ^{[5
]}

Li, Qi ^{[1
,6
]}

Yang, Chenning ^{[1
]}

Le, Yi ^{[7
]}

Xing, Jinliang ^{[8
]}

Zhang, Hongxin ^{[2
,9
]}

An, Jiaze ^{[10
]}

Jia, Weihua ^{[11
,12
]}

Kang, Longli ^{[13
]}

Zhang, Hongxing ^{[6
]}

Xie, Hui ^{[14
]}

Ye, Jiazhou ^{[15
]}

Wu, Tianzhun ^{[15
]}

He, Fuchu ^{[2
]}

Zhang, Xuejun ^{[16
,17
]}

Li, Yuanfeng ^{[1
]}

Zhou, Gangqiao ^{[1
,18
]}

机构：

[1] Beijing Inst Radiat Med, Natl Ctr Prot Sci Beijing, Beijing Proteome Res Ctr, State Key Lab Med Prote, Beijing, Peoples R China

[2] Beijing Inst Lifeom, Natl Ctr Prot Sci Beijing, Beijing Proteome Res Ctr, State Key Lab Med Prote, Beijing, Peoples R China

[3] China Japan Friendship Hosp, Dept Dermatol, Dept Pharm, Beijing, Peoples R China

[4] Chinese Peoples Liberat Army Gen Hosp, Fac Hepatobiliary Pancreat Surg, Med Ctr 1, Beijing, Peoples R China

[5] Guangxi Med Univ, Affiliated Canc Hosp, Nanning, Guangxi, Peoples R China

[6] Univ South China, Sch Med, Dept Neurosci, Hengyang, Hunan, Peoples R China

[7] Chinese Peoples Liberat Army Gen Hosp, Dept Hepatobiliary Surg, Med Ctr 5, Beijing, Peoples R China

[8] Air Force Med Univ, Expt Teaching Ctr Basic Med, State Key Lab Canc Biol, Xian, Shaanxi, Peoples R China

[9] Air Force Med Univ, Tangdu Hosp, Dept Pain Treatment, Xian, Shaanxi, Peoples R China

[10] Air Force Med Univ, Xijing Hosp, Dept Hepatobiliary Surg, Xian, Shaanxi, Peoples R China

[11] State Key Lab Oncol Southern China, Guangzhou, Guangdong, Peoples R China

[12] Sun Yat Sen Univ, Dept Expt Res, Canc Ctr, Guangzhou, Guangdong, Peoples R China

[13] Xizang Minzu Univ, Sch Med, Key Lab Mol Genet Mech & Intervent Res High Altitu, Key Lab High Altitude Environm & Genes Related Dis, Xianyang, Shaanxi, Peoples R China

[14] Chinese Peoples Liberat Army Gen Hosp, Dept Intervent Oncol, Med Ctr 5, Beijing, Peoples R China

[15] Guangxi Med Univ, Guangxi Liver Canc Diag & Treatment Engn & Technol, Dept Hepatobiliary & Pancreat Surg, Canc Hosp, Nanning, Guangxi, Peoples R China

[16] Anhui Med Univ, Affiliated Hosp 1, Dept Dermatol, Hefei, Anhui, Peoples R China

[17] Anhui Med Univ, Affiliated Hosp 1, Inst Dermatol, Hefei, Anhui, Peoples R China

[18] Nanjing Med Univ, Collaborat Innovat Ctr Personalized Canc Med, Ctr Global Hlth, Sch Publ Hlth, Nanjing, Jiangsu, Peoples R China

来源：

CELL GENOMICS | 2024年 / 4卷 / 05期

基金：

中国国家自然科学基金;

关键词：

GENOME-WIDE ASSOCIATION; DNA-REPAIR; SUSCEPTIBILITY LOCUS; READ ALIGNMENT; CANCER; EXPRESSION; NBS1; PATHOGENICITY; POLYMORPHISM; FRAMEWORK;

D O I：

10.1016/j.xgen.2024.100550

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 HCCassociated genes, including NRDE2 , RANBP17 , RTEL1 , and STEAP3 . Using NRDE2 (index rs199890497 [p.N377I], p = 1.19 3 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.

引用

页数：34

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