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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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FBXW7 Confers Radiation Survival by Targeting p53 for Degradation

Danrui Cui1, Xiufang Xiong2, Jianfeng Shu1

  • 1Key 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.

Cell Reports
|January 16, 2020
PubMed

Insights

The FBXW7 E3 ligase targets the tumor suppressor p53 for degradation after DNA damage. Inhibiting FBXW7 stabilizes p53, enhancing cancer cell sensitivity to chemotherapy and radiotherapy.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Stress Response

Background:

  • The tumor suppressor p53 is crucial for cellular stress responses and its levels are tightly regulated.
  • Ubiquitin ligases play a key role in controlling p53 stability and function.

Purpose of the Study:

  • To investigate the role of FBXW7, a component of the SCF E3 ligase complex, in regulating p53 stability.
  • To elucidate the mechanism by which FBXW7 targets p53 for degradation following DNA damage.

Main Methods:

  • Investigated the interaction between FBXW7 and p53 after exposure to ionizing radiation or etoposide.
  • Utilized small molecular inhibitors and genetic knockdown/knockout approaches to inactivate ATM and SCFFBXW7.
  • Assessed p53 protein half-life, cell-cycle arrest, and apoptosis in cancer cells.

Main Results:

  • FBXW7 directly interacts with and targets p53 for polyubiquitination and proteasomal degradation.
  • DNA damage activates ATM, which phosphorylates p53, facilitating FBXW7 binding and p53 degradation.
  • Inactivation of ATM or FBXW7 extends p53 half-life independently of MDM2, sensitizing cancer cells to DNA-damaging agents.

Conclusions:

  • FBXW7 acts as a critical regulator of p53 stability in response to DNA damage.
  • Targeting FBXW7 can enhance the efficacy of radiotherapy and chemotherapy by stabilizing p53.
  • This mechanism highlights a novel pathway for controlling p53 and offers therapeutic potential in cancer treatment.
Keywords:
ATMCRLDNA damageE3 ligaseFBXW7SCFdegradationp53radiosensitivityubiquitination

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