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 SCFFBXW7 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.
Highlights
Protein Ubiquitylation and SCF E3 Ligase With FBXW7 as a Substrate ReceptorUbiquitylation is a typical post-translational modification, that couples with proteasome, designated as ubiquitin-proteasome system (UPS), as the key proteolytic mechanism in eukaryotes for timely degradation of cellular proteins (Hershko et al, 2000)
We recently found that FBXW7 was recruited to the double strand breaks (DSBs) sites by poly(ADP-ribose) (PAR) (Zhang Q. et al, 2019) and maintained at DNA damage sites in a ATM-dependent manner upon laser irradiation to facilitate the non-homolog endjoining (NHEJ) repair (Zhang et al, 2016)
More than 40 proteins have been identified, and most of them are transcription factors that regulate a broad range of biological processes
Summary
Protein Ubiquitylation and SCF E3 Ligase With FBXW7 as a Substrate ReceptorUbiquitylation is a typical post-translational modification, that couples with proteasome, designated as ubiquitin-proteasome system (UPS), as the key proteolytic mechanism in eukaryotes for timely degradation of cellular proteins (Hershko et al, 2000). FBXW7 is a typical tumor suppressor that promotes the ubiquitylation and degradation of many cellular oncoproteins, and is frequently mutated and inactivated in many human cancers (Welcker and Clurman, 2008; Wang et al, 2012; Figure 2).
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