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NKAP acts with HDAC3 to prevent R-loop associated genome instability

Cell Death & Differentiation volume 30, pages 1811–1828 (2023)Cite this article

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Abstract

Persistent R-loop accumulation can cause DNA damage and lead to genome instability, which contributes to various human diseases. Identification of molecules and signaling pathways in controlling R-loop homeostasis provide important clues about their physiological and pathological roles in cells. Here, we show that NKAP (NF-κB activating protein) is essential for preventing R-loop accumulation and maintaining genome integrity through forming a protein complex with HDAC3. NKAP depletion causes DNA damage and genome instability. Aberrant accumulation of R-loops is present in NKAP-deficient cells and leads to DNA damage and DNA replication fork progression defects. Moreover, NKAP depletion induced R-loops and DNA damage are dependent on transcription. Consistently, the NKAP interacting protein HDAC3 exhibits a similar role in suppressing R-loop associated DNA damage and replication stress. Further analysis uncovers that HDAC3 functions to stabilize NKAP protein, independent of its deacetylase activity. In addition, NKAP prevents R-loop formation by maintaining RNA polymerase II pausing. Importantly, R-loops induced by NKAP or HDAC3 depletion are processed into DNA double-strand breaks by XPF and XPG endonucleases. These findings indicate that both NKAP and HDAC3 are novel key regulators of R-loop homeostasis, and their dysregulation might drive tumorigenesis by causing R-loop associated genome instability.

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Fig. 1: Knockdown of NKAP leads to DNA damage and genome instability.
Fig. 2: NKAP depletion induced R-loop accumulation contributes to DNA damage.
Fig. 3: Defective DNA replication in NKAP depletion cells.
Fig. 4: NKAP depletion induced R-Loops accumulation and DNA damage are dependent on transcription.
Fig. 5: Knockdown of HDAC3 results in R-loop accumulation that triggers DNA damage.
Fig. 6: Overexpression of NKAP C-terminal DUF926 domain causes R-loop accumulation and DNA damage.
Fig. 7: NKAP protein is stabilized by HDAC3 independent of its deacetylase activity.
Fig. 8: Depletion of NKAP reduces Pol II occupancy at TSS and TES sites.
Fig. 9: R-loops are processed into DNA double-strand breaks by XPF and XPG in NKAP or HDAC3 depletion cells.
Fig. 10: Working model showing the role of NKAP and HDAC3 in preventing R-loop formation and genome instability.

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The authors declare that [the/all other] data supporting the findings of this study are available within the paper [and its supplementary information files].

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Acknowledgements

We thank Prof Jun Huang for providing S9.6 antibodies during initial studies. We are grateful to Profs Jun Ma, Chih-Hung Hsu, Feng He, Pengfei Xu, Hongqing Liang and Tinggang Chew for helpful discussions.

Funding

This study was supported by the National Natural Science Foundation of China (grant 31970668) and the National Key Research and Development Program of China (2018YFC1003200).

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Authors and Affiliations

  1. Division of Human Reproduction and Developmental Genetics, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China

    Xing Zhang, Jingwei Duan, Xiaoye Jin, Cheng Wu, Xiaohang Yang & Wanzhong Ge

  2. Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China

    Xing Zhang, Jingwei Duan, Xiaoye Jin, Cheng Wu, Xiaohang Yang & Wanzhong Ge

  3. Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China

    Xing Zhang, Jingwei Duan, Yang Li, Weiguo Lu & Wanzhong Ge

  4. Department of Gynecologic Oncology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China

    Yang Li & Weiguo Lu

  5. Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China

    Weiguo Lu & Wanzhong Ge

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WG and WL contributed to the study design. XZ performed all the experiments, prepared the figures and analyzed data with the help from JD, YL, XJ and CW. WG, WL, and XY provided resource and supervision. XZ and WG wrote the paper with input from all authors.

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Zhang, X., Duan, J., Li, Y. et al. NKAP acts with HDAC3 to prevent R-loop associated genome instability. Cell Death Differ 30, 1811–1828 (2023). https://doi.org/10.1038/s41418-023-01182-5

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