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.

中文翻译：

---

FBXW7通过将p53靶向降解来赋予辐射生存能力。

肿瘤抑制因子p53在整合多种应激反应中起关键作用。因此，p53水平受多种泛素连接酶的精确调控。在这项研究中，我们报告FBXW7，SKP1-CUL1-F-box（SCF）E3连接酶的底物识别组件，在暴露于电离辐射或依托泊苷后与多聚泛素化和蛋白酶体降解作用并靶向p53。从机制上讲，DNA损伤会激活ATM，使Ser33和Ser37上的p53磷酸化，从而促进FBXW7结合以及随后p53被SCFFBXW7降解。通过小分子抑制剂或基因敲除/敲除方法使ATM或SCFFBXW7失活，以DNA损伤的方式以MDM2独立的方式延长了p53蛋白的半衰期。从生物学上讲 FBXW7失活通过稳定p53诱导细胞周期停滞和凋亡而使癌细胞对放射线或依托泊苷敏感。综上所述，我们的研究阐明了FBXW7通过p53靶向在放疗或化疗过程中赋予癌细胞存活的机制。