Tumor Suppressor FBXW7 and Its Regulation of DNA Damage Response and Repair

Abstract

The proper DNA damage response (DDR) and repair are the central molecular mechanisms for the maintenance of cellular homeostasis and genomic integrity. The abnormality in this process is frequently observed in human cancers, and is an important contributing factor to cancer development. FBXW7 is an F-box protein serving as the substrate recognition component of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase. By selectively targeting many oncoproteins for proteasome-mediated degradation, FBXW7 acts as a typical tumor suppressor. Recent studies have demonstrated that FBXW7 also plays critical roles in the process of DDR and repair. In this review, we first briefly introduce the processes of protein ubiquitylation by SCF^FBXW7 and DDR/repair, then provide an overview of the molecular characteristics of FBXW7. We next discuss how FBXW7 regulates the process of DDR and repair, and its translational implication. Finally, we propose few future perspectives to further elucidate the role of FBXW7 in regulation of a variety of biological processes and tumorigenesis, and to design a number of approaches for FBXW7 reactivation in a subset of human cancers for potential anticancer therapy.

Keywords: DDR; DNA repair; FBXW7; cancer; ubiquitylation.

FIGURE 1

Schematics of SCF, FBXW7, and FBXW7 isoforms. (A) SCF^FBXW7 consists of a scaffold cullin-1 (CUL-1), an adaptor SKP1, a RING-domain protein (RBX1/RBX2), and a substrate-receptor F-box protein (FBXW7). Shown is SCF^FBXW7 complex in FBXW7 dimerization format for ubiquitylation of a substrate. (B) Three FBXW7 isoforms (α, β, and γ) with domain alignment. NLS, nuclear localization signal; TMD, transmembrane domain; DD, dimerization domain.

FIGURE 2

FBXW7 mutation frequency in human cancers and their distributions. (A) FBXW7 mutation frequency in different types of human cancer, analyzed from cBioPortal Database (https://www.cbioportal.org/). (B) Distribution of FBXW7 mutations in the FBXW7 encoding region. Mutations detected in more than 15 cancer samples are annotated, and three most frequent mutation hotspots, R465, R479, and R505 are highlighted in red.

FIGURE 3

FBXW7 in DNA damage responses. (A) Negative feedback loop between FBXW7 and p53. Under unstressed condition, p53 level is low due to targeted degradation by MDM2 E3 ligase. Upon DNA damage, p53 protein is accumulated to transcriptionally induce FBXW7 expression; the induced FBXW7 then promotes p53 ubiquitylation and degradation after ATM-mediated p53 phosphorylation at Ser^33/37 residues (Cui et al., 2020). (B) PLK1 degradation by FBXW7 upon DDR. Under unstressed condition, PLK1 was transcriptionally induced by N-MYC. PLK also phosphorylates FBXW7 to trigger its self-ubiquitylation and cause N-MYC accumulation. Upon DNA damage, ATM/ATR phosphorylates PLK1 at Thr²¹⁴, which facilitated FBXW7 binding and subsequent ubiquitylation and degradation. (C) FBXW7 degrades SOX9 upon DDR. Under unstressed condition, SOX9 acts as a transcription factor. Upon DNA damage, SOX9 was phosphorylated at Thr^236/240 by GSK3β, which facilitated FBXW7 binding and subsequent ubiquitylation and degradation. (D) FBXW7 degrades BLM upon DDR. Upon DNA damage, BLM was sequentially phosphorylated at Thr¹⁸² by CHK1/2, and at Thr¹⁷¹ and Ser¹⁷⁵ by GSK3β/CDK2, which facilitated FBXW7 binding and subsequent ubiquitylation and degradation. TF, Transcription factor.

FIGURE 4

FBXW7 in regulation of DNA repair. Under unstressed condition, FAAP20 binds FANCA to facilitate mono-ubiquitylation of FANCD2. Upon DDR, FAAP20 was phosphorylated by GSK3β to facilitate FBXW7 binding and ubiquitylation. On the other hand, DNA-PKcs phosphorylated XRCC4, whereas ATM phosphorylated FBXW7. At the damage site, FBXW7 promoted XRCC4 polyubiquitylation via the K63 linkage to facilitate recruitment of Ku70/Ku80 for NHEJ repair.

FIGURE 5

Future perspectives. Five future directions are proposed to further broaden our understanding of FBXW7 functions: (1) Identification and characterization of new FBXW7 substrates; (2) Identification and characterization of FBXW7 binding proteins; (3) Functional characterization of FBXW7 isoforms (α, β, and γ); (4) Tissue specific role of Fbxw7 in tumorigenesis using mouse cKO or KI models; (5) Target human cancers by reactivating FBXW7. See text for details.