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TRIM24 is critical for the cellular response to DNA double-strand breaks through regulating the recruitment of MRN complex

Oncogene volume 42, pages 586–600 (2023)Cite this article

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Abstract

The MRE11-RAD50-NBS1 (MRN) complex plays a crucial role in DNA double-strand breaks (DSBs) sensing and initiation of signaling cascades. However, the precise mechanisms by which the recruitment of MRN complex is regulated has yet to be elucidated. Here, we identified TRIpartite motif-containing protein 24 (TRIM24), a protein considered as an oncogene overexpressed in cancers, as a novel signaling molecule in response to DSBs. TRIM24 is essential for DSBs-induced recruitment of MRN complex and activation of downstream signaling. In the absence of TRIM24, MRN mediated DSBs repair is remarkably diminished. Mechanistically, TRIM24 is phosphorylated by ataxia-telangiectasia mutated (ATM) and then recruited to DSBs sites, facilitating the accumulation of the MRN components to chromatin. Depletion of TRIM24 sensitizes human hepatocellular carcinoma cells to cancer therapy agent-induced apoptosis and retards the tumor growth in a subcutaneous xenograft tumor mouse model. Together, our data reveal a novel function of TRIM24 in response to DSBs through regulating the MRN complex, which suggests that TRIM24 may be a potential therapeutic molecular target for tumor treatment.

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Fig. 1: TRIM24 is involved in DSBs repair.
Fig. 2: TRIM24 knockdown dampens the activation of repair signaling initiated by DSBs.
Fig. 3: TRIM24 interacts with MRE11 directly.
Fig. 4: TRIM24 is recruited to damaged DNA and subsequently regulates recruitments of MRN complex.
Fig. 5: Recruitment of TRIM24 to DNA damage sites depends on ATM.
Fig. 6: ATM-dependent phosphorylation of TRIM24 at S768 and S808 is critical for DSBs-induced DDR.
Fig. 7: TRIM24 is important for the resistance of hepatocellular carcinoma cells to DSBs.
Fig. 8: Deletion of TRIM24 sensitizes HCC cells to DSBs-induced apoptosis in xenograft mouse model.

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Data availability

Netphos 3.1 is an online database for the prediction of kinases (https://services.healthtech.dtu.dk/service.php?NetPhos-3.1). RNA-seq data and corresponding clinical information of HCC were extracted from The Cancer Genome Atlas (TCGA) (https://portal.gdc.cancer.gov/).

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Acknowledgements

We are grateful to Michelle C. Barton (University of Texas M. D. Anderson Cancer Center) for providing the wild-type and TRIM24 knockout MEF cells; Zhiyong Mao (Tongji University) for providing the HR reporter plasmids; the “Furong Scholar Program” provided by Department of Education of Hunan province; the Cancer Genome Atlas Program for the database.

Funding

This work was supported by National Natural Science Foundation of China [31900561, 32170726 and 32100580] to KF and YW; Hunan Provincial Science and Technology Department [2021JJ20094] to KF; Central South University [2020CX016] to KF. Funding for open access charge: National Natural Science Foundation of China.

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  1. These authors contributed equally: Ya Wang, Yuanbing Yao.

Authors and Affiliations

  1. Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China

    Ya Wang, Yuanbing Yao, Shichao Long, Yuqiao Chen & Kai Fu

  2. Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410008, Hunan, China

    Ya Wang, Qunhui Wei & Kai Fu

  3. Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, 410008, Hunan, China

    Ya Wang & Kai Fu

  4. National Clinical Research Center for Geriatric Disorders, Changsha, 410008, Hunan, China

    Yuanbing Yao & Kai Fu

  5. Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China

    Yuanbing Yao, Rong Tan & Kai Fu

  6. Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, 410008, Hunan, China

    Jinru Xie & Rong Tan

  7. Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Wei Jiang & Dongbo Wu

  8. Department of Nutrition and Health, China Agricultural University, 100193, Beijing, China

    Qian Zhang

  9. The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China

    Shuai Xiao

  10. Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 21025, USA

    Fengyi Wan

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Contributions

KF, FW and SX performed study concept and design; YW, YY, QW, SL, WJ and DW performed experiments and analyzed the data; YC revised the paper; JX, RT and QZ provided technical and material support. KF, YW and YY write, reviewed and revised the paper; KF provided acquisition, analysis and interpretation of data, and statistical analysis. All authors read and approved the final paper.

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Correspondence to Kai Fu.

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The study is approved by the Ethics Committee of West China Hospital, Sichuan University.

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Wang, Y., Yao, Y., Wei, Q. et al. TRIM24 is critical for the cellular response to DNA double-strand breaks through regulating the recruitment of MRN complex. Oncogene 42, 586–600 (2023). https://doi.org/10.1038/s41388-022-02580-8

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