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DNA damage-induced translocation of mitochondrial factor HIGD1A into the nucleus regulates homologous recombination and radio/chemo-sensitivity

Oncogene volume 41, pages 1918–1930 (2022)Cite this article

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Abstract

HIGD1A is an important mitochondrial protein recently shown to have a novel nuclear localization under severe stress. However, whether this protein is also associated with the DNA damage response has rarely been studied. Here, we reported that DSBs-induced the translocation of mitochondrial HIGD1A to the nucleus is dependent on nuclear pore complex (NPCs), which finally promotes HR and radio/chemo-resistance. Importantly, NUP93 and HIGD1A physically interact and the interaction domain with NUP93 is located at residues 46–60 of HIGD1A. Chromatin-enriched HIGD1A can then directly interact with RPA. During the early stages of HR, HIGD1A promotes the loading of RPA to DSBs and activates the DNA damage-dependent chromatin association of RAD9-RAD1-HUS1 complex (9-1-1), which stimulates the ATR-Chk1-dependent G2/M DNA damage checkpoint. After facilitating RPA-ssDNA binding, HIGD1A in turn inhibits abnormal persistence of RPA1 foci by promoting ubiquitination of RPA1 and inducing its eventual proteasomal degradation. In addition, we have identified clinical drug Preveon associated with the HIGD1A-NUP93 interaction domain using a virtual screening approach. This compound directly interacted with HIGD1A, which was verified by NMR, and then inhibited HIGD1A translocation. Collectively, we demonstrate a novel role for HIGD1A in DSBs and provide rationale for using HIGD1A inhibitors as cancer therapeutics.

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Fig. 1: HIGD1A is required for DNA damage repair.
Fig. 2: NUP93 physically interacts with HIGD1A and allows HIGD1A localization to the nucleus in response to DSBs.
Fig. 3: HIGD1A regulates homologous repair of DSBs.
Fig. 4: HIGD1A promotes the loading of RPA1 to DSBs.
Fig. 5: HIGD1A facilitates the removal of RPA1 timely from DSBs.
Fig. 6: HIGD1A depletion blocks the interaction of the RAD9-RAD1-HUS1 complex with RPA1 and inhibits the subsequent ATR-Chk1 axis.
Fig. 7: HIGD1A mediates chemosensitivity in cancer cells.
Fig. 8: Targeting HIGD1A enhances the efficacy of radiotherapy and chemotherapy in vivo.
Fig. 9: Virtual screening of drugs that block HIGD1A localization to the nucleus.
Fig. 10: Schematic illustration of the mechanism of HIGD1A regulating HR.

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Acknowledgements

This work was supported by the National Science Fund for Excellent Young Scholars (12122510), the National Natural Science Foundation of China (32171240, 11835014, and 31870845), the HFIPS Director’s Fund (Grant No. YZJJZX202014) and the CAS Pioneer Hundred Talents Program (GZ).

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Authors and Affiliations

  1. High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, China

    Bin Chen, Feng Xu, Yang Gao, Guanshuo Hu, Kaili Zhu, An Xu, Shaopeng Chen, Lijun Wu & Guoping Zhao

  2. University of Science and Technology of China, Hefei, Anhui, 230026, China

    Bin Chen, Feng Xu, Yang Gao, Guanshuo Hu & Kaili Zhu

  3. The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China

    Huayi Lu

  4. Information Materials and Intelligent Sensing Laboratory of Anhui Province, Institutes of Physical Science and Information Technology, Anhui University, Hefei, Anhui, 230601, China

    Lijun Wu

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  1. Bin Chen
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Contributions

GZ and BC conceived of the study; BC, FX, YG, GH, KZ, and HL conducted experiments; SC, AX and LW analyzed and interpreted the data; GZ and BC wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Guoping Zhao.

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Chen, B., Xu, F., Gao, Y. et al. DNA damage-induced translocation of mitochondrial factor HIGD1A into the nucleus regulates homologous recombination and radio/chemo-sensitivity. Oncogene 41, 1918–1930 (2022). https://doi.org/10.1038/s41388-022-02226-9

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