2. Academic Validation
  3. FBXW7 Confers Radiation Survival by Targeting p53 for Degradation

FBXW7 Confers Radiation Survival by Targeting p53 for Degradation

  • Cell Rep. 2020 Jan 14;30(2):497-509.e4. doi: 10.1016/j.celrep.2019.12.032.
Danrui Cui 1,  Xiufang Xiong 2,  Jianfeng Shu 1,  Xiaoqing Dai 1,  Yi Sun 3,  Yongchao Zhao 4
Affiliations

Affiliations

  • 1 Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China; Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 3 Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China; Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 4 Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. Electronic address: yongchao@zju.edu.cn.
PMID: 31940492 DOI: 10.1016/j.celrep.2019.12.032
Abstract

The tumor suppressor p53 plays a critical role in integrating a wide variety of stress responses. Therefore, p53 levels are precisely regulated by multiple ubiquitin ligases. In this study, we report that FBXW7, a substrate recognition component of the SKP1-CUL1-F-box (SCF) E3 Ligase, interacts with and targets p53 for polyubiquitination and proteasomal degradation after exposure to ionizing radiation or etoposide. Mechanistically, DNA damage activates ATM to phosphorylate p53 on Ser33 and Ser37, which facilitates the FBXW7 binding and subsequent p53 degradation by SCFFBXW7. Inactivation of ATM or SCFFBXW7 by small molecular inhibitors or genetic knockdown/knockout approaches extends the p53 protein half-life upon DNA damage in an MDM2-independent manner. Biologically, FBXW7 inactivation sensitizes Cancer cells to radiation or etoposide by stabilizing p53 to induce cell-cycle arrest and Apoptosis. Taken together, our study elucidates a mechanism by which FBXW7 confers Cancer cell survival during radiotherapy or chemotherapy via p53 targeting.

Keywords

ATM; CRL; DNA damage; E3 ligase; FBXW7; SCF; degradation; p53; radiosensitivity; ubiquitination.

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