2. Academic Validation
  3. NKAP acts with HDAC3 to prevent R-loop associated genome instability

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

  • Cell Death Differ. 2023 Jun 15. doi: 10.1038/s41418-023-01182-5.
Xing Zhang 1 2 3,  Jingwei Duan 1 2 3,  Yang Li 3 4,  Xiaoye Jin 1 2,  Cheng Wu 1 2,  Xiaohang Yang 1 2,  Weiguo Lu 5 6 7,  Wanzhong Ge 8 9 10 11
Affiliations

Affiliations

  • 1 Division of Human Reproduction and Developmental Genetics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China.
  • 2 Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China.
  • 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.
  • 4 Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China.
  • 5 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. lbwg@zju.edu.cn.
  • 6 Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China. lbwg@zju.edu.cn.
  • 7 Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China. lbwg@zju.edu.cn.
  • 8 Division of Human Reproduction and Developmental Genetics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China. wanzhongge@zju.edu.cn.
  • 9 Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China. wanzhongge@zju.edu.cn.
  • 10 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. wanzhongge@zju.edu.cn.
  • 11 Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China. wanzhongge@zju.edu.cn.
PMID: 37322264 DOI: 10.1038/s41418-023-01182-5
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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