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

被引：1

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

共 50 条

[21] Cracking the homologous recombination deficiency code: how to identify responders to PARP inhibitors
Paulet, Lola
Trecourt, Alexis
Leary, Alexandra
Peron, Julien
Descotes, Francoise
Devouassoux-Shisheboran, Mojgan
Leroy, Karen
You, Benoit
Lopez, Jonathan
EUROPEAN JOURNAL OF CANCER, 2022, 166 : 87 - 99
[22] EMolecular and Clinicopathologic Analysis of Hepatocellular Carcinoma with Homologous Recombination Deficiency
Chou, Eunice
Davarpanah, Amir
Yin, Feng
Chen, Wei
Xue, Yue
Hu, Jian
Teng, Yong
Zhang, Linsheng
Deeb, Kristin
Saxena, Romil
Farris, Alton B.
Krasinskas, Alyssa
Zheng, Wei
LABORATORY INVESTIGATION, 2024, 104 (03) : S1651 - S1652
[23] ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors
Shen, Jianfeng
Peng, Yang
Wei, Leizhen
Zhang, Wei
Yang, Lin
Lan, Li
Kapoor, Prabodh
Ju, Zhenlin
Mo, Qianxing
Shih, Ie-Ming
Uray, Ivan P.
Wu, Xiangwei
Brown, Powel H.
Shen, Xuetong
Mills, Gordon B.
Peng, Guang
CANCER DISCOVERY, 2015, 5 (07) : 752 - 767
[24] Ovarian Cancer Therapy: Homologous Recombination Deficiency as a Predictive Biomarker of Response to PARP Inhibitors
Miller, Rowan E.
Elyashiv, Osnat
El-Shakankery, Karim H.
Ledermann, Jonathan A.
ONCOTARGETS AND THERAPY, 2022, 15 : 1105 - 1117
[25] KRAS pharmacological blockade elicits tumoral homologous recombination deficiency exploitable with PARP inhibitors
Welch, C.
Novoa, G.
Llorente Llorente, S.
Santos Ramos, A.
Sogari, A.
Fernandez Lagos, A.
Fileu, I.
Guruceaga, E.
Calvo, A.
Bakartxo Otegui, N.
Battuello, P.
Crisafulli, G.
Ambrogio, C.
Santamaria, D.
Bardelli, A.
Tian, T.
Ferrer, I.
Russo, M.
Vicent, S.
EUROPEAN JOURNAL OF CANCER, 2024, 211 : S92 - S93
[26] Low dose DNA methyltransferase inhibitors potentiate PARP inhibitors in homologous recombination repair deficient tumors
Pacaud, Romain
Thomas, Scott
Chaudhuri, Sibapriya
Lazar, Ann
Timmerman, Luika A.
Munster, Pamela N.
BREAST CANCER RESEARCH, 2025, 27 (01)
[27] ATR, CHK1 and WEE1 inhibitors cause homologous recombination repair deficiency to induce synthetic lethality with PARP inhibitors
Smith, Hannah L.
Willmore, Elaine
Prendergast, Lisa
Curtin, Nicola J.
BRITISH JOURNAL OF CANCER, 2024, 131 (05) : 905 - 917
[28] Natural product Pulsatilla saponin D sensitizes BRCA-proficient ovarian cancers to PARP inhibitors through inhibiting homologous recombination repair
Lin, Shengbin
Sun, Binghe
Zhu, Yin
Huang, Yi
Qin, Yu
Yao, Nan
Liu, Yongzhu
Chen, Guo
JOURNAL OF PHARMACY AND PHARMACOLOGY, 2025,
[29] A Cyclin-Dependent Kinase Inhibitor, Dinaciclib, Impairs Homologous Recombination and Sensitizes Multiple Myeloma Cells to PARP Inhibition
Alagpulinsa, David A.
Ayyadevara, Srinivas
Yaccoby, Shmuel
Reis, Robert J. Shmookler
MOLECULAR CANCER THERAPEUTICS, 2016, 15 (02) : 241 - 250
[30] Testing for homologous recombination repair or homologous recombination deficiency for poly (ADP-ribose) polymerase inhibitors: A current perspective
Herzog, Thomas J.
Vergote, Ignace
Gomella, Leonard G.
Milenkova, Tsveta
French, Tim
Tonikian, Raffi
Poehlein, Christian
Hussain, Maha
EUROPEAN JOURNAL OF CANCER, 2023, 179 : 136 - 146

← 1 2 3 4 5 →