FBXW7 Confers Radiation Survival by Targeting p53 for Degradation

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.