VCP’s nuclear journey: Initiated by interacting with KPNB1 to repair DNA damage
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (14)
Zhichao Xing
Division of Thyroid Surgery, Department of General Surgery and Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University
Xiaoying Cai
Department of Biotherapy, Cancer Center and State Key laboratory of Biotherapy, West China Hospital, Sichuan University
Ting He
Division of Thyroid Surgery, Department of General Surgery and Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University
Peiheng Li
Division of Thyroid Surgery, Department of General Surgery and Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University
Jun He
Yuxuan Qiu
Department of Ultrasound, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University
Na Li
Li Mi
Division of Thyroid Surgery, Department of General Surgery and Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University
Ruixi Li
Division of Thyroid Surgery, Department of General Surgery and Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University
Jingqiang Zhu
Division of Thyroid Surgery, Department of General Surgery and Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University
Zhihui Li
Anping Su
Division of Thyroid Surgery, Department of General Surgery and Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University
Haoyu Ye
Department of Biotherapy, Cancer Center and State Key laboratory of Biotherapy, West China Hospital, Sichuan University
Wenshuang Wu
Division of Thyroid Surgery, Department of General Surgery and Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University