NKAP acts with HDAC3 to prevent R-loop associated genome instability
NKAP acts with HDAC3 to prevent R-loop associated genome instability
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DOI：
10.1038/s41418-023-01182-5
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发表时间：
2023-06
影响因子：
12.4
通讯作者：
Xing Zhang;Jingwei Duan;Yang Li;Xiaoye Jin;Cheng Wu;Xiaohang Yang;Weiguo Lu;Wanzhong Ge
中科院分区：
文献类型：
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作者：
Xing Zhang;Jingwei Duan;Yang Li;Xiaoye Jin;Cheng Wu;Xiaohang Yang;Weiguo Lu;Wanzhong Ge
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.
