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Review
. 2023 Sep 13;11(9):2527.
doi: 10.3390/biomedicines11092527.

RNF126, 168 and CUL1: The Potential Utilization of Multi-Functional E3 Ubiquitin Ligases in Genome Maintenance for Cancer Therapy

Hae Ryung Chang  1
Affiliations
Review

RNF126, 168 and CUL1: The Potential Utilization of Multi-Functional E3 Ubiquitin Ligases in Genome Maintenance for Cancer Therapy

Hae Ryung Chang. Biomedicines. .

Abstract

Ubiquitination is a post-translational modification (PTM) that is involved in proteolysis, protein-protein interaction, and signal transduction. Accumulation of mutations and genomic instability are characteristic of cancer cells, and dysfunction of the ubiquitin pathway can contribute to abnormal cell physiology. Because mutations can be critical for cells, DNA damage repair, cell cycle regulation, and apoptosis are pathways that are in close communication to maintain genomic integrity. Uncontrolled cell proliferation due to abnormal processes is a hallmark of cancer, and mutations, changes in expression levels, and other alterations of ubiquitination factors are often involved. Here, three E3 ubiquitin ligases will be reviewed in detail. RNF126, RNF168 and CUL1 are involved in DNA damage response (DDR), DNA double-strand break (DSB) repair, cell cycle regulation, and ultimately, cancer cell proliferation control. Their involvement in multiple cellular pathways makes them an attractive candidate for cancer-targeting therapy. Functional studies of these E3 ligases have increased over the years, and their significance in cancer is well reported. There are continuous efforts to develop drugs targeting the ubiquitin pathway for anticancer therapy, which opens up the possibility for these E3 ligases to be evaluated for their potential as a target protein for anticancer therapy.

Keywords: CUL1; RNF126; RNF168; apoptosis; cell cycle; drug resistance; genome maintenance; targeted cancer therapy; tumor suppressors; ubiquitin pathway.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
E3 ubiquitin ligase in DNA damage response and DNA double-strand break repair. Simplified depiction of E3 ligases, RNF8, RNF168, RNF126 and SCF complex (CUL1) are shown. The three main E3 ligases discussed in this review are shown in glowing red. RNF168 is recruited to RNF8-ubiquitinated γH2AX. 53BP1 can interact with the poly-ubiquitin chain attached by RNF168, or γH2AX, which is methylated and mono-ubiquitinated. The binding of 53BP1 recruits the NHEJ factor, KU 70/80 complex. The KU complex recruits DNA-PKcs, and then downstream factors. RNF126 and the SCF complex have been reported to ubiquitinate KU80 for ubiquitin-mediated proteolysis. Degradation of KU80 ensures the disassembly of the KU complex and repair of the DSB. 53BP1 binding to the poly-ubiquitinated γH2AX competes with RAP80, which recruits BRCA1-BARD1. This recruits HR factors for end resection, and exposes single-stranded DNA (ssDNA) ends. RPA binds and protects the ssDNA ends, and the BRCA1-PALB2-BRCA2 complex is recruited, bringing RAD51 to replace RPA. Downstream events allow for high-fidelity repair using homologous DNA strands. RNF126 functions in-between RNF8 and RNF168, inhibiting the recruitment of 53BP1. It is also involved in the transcription activation of BRCA1. (Created with Biorender.com accessed on 3 August 2023).
Figure 2
Figure 2
Genetic alteration of CUL1 and FBXW7 in various cancers. (A). Genetic alteration of SCF complex factors from the ICGC/TCGA 2020 pan-cancer study [110]. CUL1 was altered in 9% of all cases, and FBXW7 was altered in 7%. OncoPrint was generated using cBioPortal [108,109], and the total length of patient cases depicted is reduced for fit. (B). Percentage of CUL1 alteration across various cancer types. (C). Percentage of FBXW7 alteration across various cancer types.
Figure 3
Figure 3
Crystal structure of Cdc/FBXW7 and inhibitor SCF-I2 (PDB ID: 3MKS). (A). SCF-I2 is bound to Cdc4. (B,C). Skp1-Cdc4 without and with SCF-I2, respectively. (Figure generated using RCSB PDB Mol* Viewer (WebGL version) [175,176].
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