VCP’s nuclear journey: Initiated by interacting with KPNB1 to repair DNA damage

DNA damage repair (DDR) is essential for cancer cell survival and treatment resistance, making it a critical target for tumor therapy. The eukaryotic AAA+ adenosine triphosphatase valosin-containing protein (VCP), which is transported from the cytoplasm into the nucleus, plays a critical role in the DDR process. However, the nuclear translocation and molecular mechanism of VCP for DDR remain elusive. Here, we define VCP as a KPNB1 interacting protein through a combination of chemical and immunoprecipitation mass spectrometry approaches. Further biochemical studies elucidate that KPNB1 directly transports VCP into the nucleus. We also identify withaferin A (WA) as a small molecule that can retard VCP nuclear localization via covalent binding to CYS 158 of KPNB1. Further studies verify WA as an effective antitumor drug candidate via blocking VCP nuclear localization to impact on the DDR pathway in vivo. Our findings underly the unclear VCP's role in DDR in a KPNB1-dependent manner and provide an important theoretical basis for developing small-molecule inhibitors targeting this process.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-05-08
DOI
https://doi.org/10.1073/pnas.2416045122
Citations
2
Primary Topic
DNA Repair Mechanisms
Type
article
Field-Weighted Citation Impact
1.61

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article

VCP’s nuclear journey: Initiated by interacting with KPNB1 to repair DNA damage

Haoyu Ye, Peiheng Li, Xiaoying Cai, Yuxuan Qiu et al.
2 citations
Proceedings of the National Academy of Sciences
DNA Repair Mechanisms
1.61
article

VCP’s nuclear journey: Initiated by interacting with KPNB1 to repair DNA damage

Haoyu Ye, Peiheng Li, Xiaoying Cai, Yuxuan Qiu, Anping Su, Ruixi Li, Jingqiang Zhu, Zhichao Xing, Wenshuang Wu, Na Li, Jun He, Li Mi, Zhihui Li, Ting He
article en
2 citations

Abstract

DNA damage repair (DDR) is essential for cancer cell survival and treatment resistance, making it a critical target for tumor therapy. The eukaryotic AAA+ adenosine triphosphatase valosin-containing protein (VCP), which is transported from the cytoplasm into the nucleus, plays a critical role in the DDR process. However, the nuclear translocation and molecular mechanism of VCP for DDR remain elusive. Here, we define VCP as a KPNB1 interacting protein through a combination of chemical and immunoprecipitation mass spectrometry approaches. Further biochemical studies elucidate that KPNB1 directly transports VCP into the nucleus. We also identify withaferin A (WA) as a small molecule that can retard VCP nuclear localization via covalent binding to CYS 158 of KPNB1. Further studies verify WA as an effective antitumor drug candidate via blocking VCP nuclear localization to impact on the DDR pathway in vivo. Our findings underly the unclear VCP's role in DDR in a KPNB1-dependent manner and provide an important theoretical basis for developing small-molecule inhibitors targeting this process.

Proceedings of the National Academy of SciencesVol. 122(19)
Sichuan University (CN), Westlake University (CN), West China Hospital of Sichuan University (CN), Affiliated Hangzhou First People's Hospital, Westlake University, School of Medicine (CN), State Key Laboratory of Biotherapy
Sichuan University, Sichuan Province Science and Technology Support Program, West China Hospital, Sichuan University
Good health and well-being
Openalex Percentile: Top 17%
DNA Repair Mechanisms
1.61
DOIOpen Access PDFOpenAlex
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