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FBXW7 Confers Radiation Survival by Targeting p53 for Degradation

35 Pages Posted: 31 Jul 2019 Sneak Peek Status: Published

See all articles by Danrui Cui

Danrui Cui

Zhejiang University - Key Laboratory of Combined Multi-Organ Transplantation

Xiufang Xiong

Zhejiang University - Institute of Translational Medicine

Yi Sun

Zhejiang University - Institute of Translational Medicine; University of Michigan at Ann Arbor - Division of Radiation and Cancer Biology

Yongchao Zhao

Zhejiang University - Key Laboratory of Combined Multi-Organ Transplantation; Zhejiang University - Cancer Institute

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Abstract

The tumor suppressor p53 plays a critical role in integrating a wide variety of stress responses that induce cell growth arrest, apoptosis, and senescence and lead to tumor suppression. Therefore, p53 levels are precisely regulated by multiple ubiquitin ligases, including the master ligase, MDM2. 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 E3 ligase. Inactivation of ATM or FBXW7 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 new mechanism by which FBXW7 confers cancer cell survival during radiotherapy or chemotherapy via p53 targeting. Our study also implies that cancer patients with FBXW7 inactivation, coupled with wild-type p53, might be more sensitive to chemo-radiation, leading to a better survival.

Keywords: FBXW7, p53, E3 ligase, DNA damage, radiosensitivity

Suggested Citation

Cui, Danrui and Xiong, Xiufang and Sun, Yi and Zhao, Yongchao, FBXW7 Confers Radiation Survival by Targeting p53 for Degradation (July 30, 2019). Available at SSRN: https://ssrn.com/abstract=3428721 or http://dx.doi.org/10.2139/ssrn.3428721
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Danrui Cui

Zhejiang University - Key Laboratory of Combined Multi-Organ Transplantation

Hangzhou, Zhejiang 310003
China

Xiufang Xiong

Zhejiang University - Institute of Translational Medicine

China

Yi Sun

Zhejiang University - Institute of Translational Medicine ( email )

China

University of Michigan at Ann Arbor - Division of Radiation and Cancer Biology ( email )

1500 E Medical Center Dr.
UH B2C490
Ann Arbor, 48109-5010
United States

Yongchao Zhao (Contact Author)

Zhejiang University - Key Laboratory of Combined Multi-Organ Transplantation ( email )

Hangzhou, Zhejiang 310003
China

Zhejiang University - Cancer Institute ( email )

China

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