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Int J Biol Sci 2022; 18(6):2515-2526. doi:10.7150/ijbs.70960 This issue Cite

Research Paper

IKZF1 selectively enhances homologous recombination repair by interacting with CtIP and USP7 in multiple myeloma

Meng Liu^1#, Ying Zhang^2#, Yunzhao Wu¹, Jin Jin³, Yang Cao⁴, Zhixiao Fang⁵, Lou Geng⁶, Li Yang¹, Miao Yu¹, Zhilei Bu⁷, Yanjie Ji¹, Huizhuang Shan¹, Zhihui Zou¹, Ligen Liu¹, Yingying Wang¹, Youping Zhang¹, Yin Tong², Hanzhang Xu¹, Hu Lei¹, Wei Liu^2✉, Fenghou Gao^6✉, Yingli Wu^1✉

1. Hongqiao International Institute of Medicine, Shanghai Tongren Hospital / Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
2. Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
3. Department of Ultrasound, Second Affiliated Hospital of Zhejiang University, Hangzhou 310009, China.
4. Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province 213003, China.
5. Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
6. Department of Oncology, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201999, China.
7. Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai 200433, China.
#These authors contributed equally to this work.

✉ Corresponding authors: Yingli Wu, M.D., Ph.D., Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Phone: 0086-21-63846590-776916; Fax: 0086-21-64154900, E-mail: wuyingliedu.cn; Fenghou Gao, Ph.D., Department of Oncology, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201999, China. Phone: 0086-21-56691101-6964; Fax: 0086-21-56693614, E-mail: fenghougaocom; Wei Liu, Ph.D., Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China. Phone: 0086-21-36126284; Fax: 0086-21-63243749, E-mail: bsjysedu.cn. More

Abstract

Rationale: In multiple myeloma (MM), the activities of non-homologous end joining (NHEJ) and homologous recombination repair (HR) are increased compared with healthy controls. Whether and how IKZF1 as an enhancer of MM participates in the DNA repair pathway of tumor cells remains elusive.

Methods: We used an endonuclease AsiSI-based system and quantitative chromatin immunoprecipitation assay (qChIP) analysis to test whether IKZF1 is involved in DNA repair. Immunopurification and mass spectrometric (MS) analysis were performed in MM1.S cells to elucidate the molecular mechanism that IKZF1 promotes DNA damage repair. The combination effect of lenalidomide or USP7 inhibitor with PARP inhibitor on cell proliferation was evaluated using MM cells in vitro and in vivo.

Results: We demonstrate that IKZF1 specifically promotes homologous recombination DNA damage repair in MM cells, which is regulated by its interaction with CtIP and USP7. In this process, USP7 could regulate the stability of IKZF1 through its deubiquitinating activity. The N-terminal zinc finger domains of IKZF1 and the ubiquitin-like domain of USP7 are necessary for their interaction. Furthermore, targeted inhibition IKZF1 or USP7 could sensitize MM cells to PARP inhibitor treatment in vitro and in vivo.

Conclusions: Our findings identify USP7 as a deubiquitinating enzyme for IKZF1 and uncover a new function of IKZF1 in DNA damage repair. In translational perspective, the combination inhibition of IKZF1 or USP7 with PARP inhibitor deserves further evaluation in clinical trials for the treatment of MM.

Keywords: IKZF1, DNA repair, HR, USP7, multiple myeloma

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