Ubiquitination Links DNA Damage and Repair Signaling to Cancer Metabolism

Abstract

Changes in the DNA damage response (DDR) and cellular metabolism are two important factors that allow cancer cells to proliferate. DDR is a set of events in which DNA damage is recognized, DNA repair factors are recruited to the site of damage, the lesion is repaired, and cellular responses associated with the damage are processed. In cancer, DDR is commonly dysregulated, and the enzymes associated with DDR are prone to changes in ubiquitination. Additionally, cellular metabolism, especially glycolysis, is upregulated in cancer cells, and enzymes in this metabolic pathway are modulated by ubiquitination. The ubiquitin-proteasome system (UPS), particularly E3 ligases, act as a bridge between cellular metabolism and DDR since they regulate the enzymes associated with the two processes. Hence, the E3 ligases with high substrate specificity are considered potential therapeutic targets for treating cancer. A number of small molecule inhibitors designed to target different components of the UPS have been developed, and several have been tested in clinical trials for human use. In this review, we discuss the role of ubiquitination on overall cellular metabolism and DDR and confirm the link between them through the E3 ligases NEDD4, APC/C^CDH1, FBXW7, and Pellino1. In addition, we present an overview of the clinically important small molecule inhibitors and implications for their practical use.

Keywords: DNA damage response; DNA repair; E3 ligase; cancer metabolism; therapeutics; ubiquitination.

Figure 1

Ubiquitination regulates DSB repair pathway. (A) DSBs can be repaired by NHEJ and HR. Both pathways initiate with recruitment of MRN complex and E3 ubiquitin ligases RNF8 and RNF168. DNA repair pathway choice is determined by recruitment of 53BP1 or BRCA1 in H2A. 53BP1 leads NHEJ in G1 phase, whereas BRCA1 leads HR in S/G2 phase. (B) In NHEJ, Ku recruits DNA-PKcs. 53BP1 that phosphorylated by ATM binds with PTIP and RIF1. 53BP1 and PTIP recruit Artemis, which trims the DNA ends. Additional NHEJ factors assemble and ligate DNA breaks. During NHEJ, HR is suppressed through ubiquitin-mediated degradation of CtIP by APC/C^Cdh1 and inhibition of BRCA1 by 53BP1-RIF1 and CRL3^KEAP1. (C) In HR, RNF138 ubiquitinates Ku for degradation. BRCA1, MRN, and CtIP form a complex, and ubiquitinated CtIP takes part in end resection. Then, ssDNA tail is bound by RPA. When PALB2 is deubiquitinated by USP11, BRCA1-PALB2-BRCA2 complex mediate replacement of RPA into RAD51. RAD51-coated filaments invade the homologous strand. Finally, DNA synthesis is completed with ubiquitin-mediated degradation of RAD51 by RFWD3. During HR, NHEJ is suppressed through inhibition of 53BP1 by BRCA1.

Figure 2

E3 ubiquitin ligases link DDR-related proteins and cancer metabolism-related proteins. (A) RNAPII functionally stalled at the DNA lesion is ubiquitinated by NEDD4 for proteasomal degradation, allowing DNA repair and restarting transcription. (B) PTEN acts as an antagonist to PI3K; however, NEDD4 ubiquitinates PTEN to downregulate its activity, allowing PI3K/AKT signaling. (C) E2F1 accumulation during G1/S transition is controlled by APC/C^cdh1 mediated ubiquitination. (D) IDH3β and PFKFB3, related to glucose metabolism, undergo ubiquitination-mediated degradation by APC/C^cdh1. (E) FBXW7-mediated K48 ubiquitination of p53 leads to its degradation and promotes cell cycle recovery. (F) Upon DNA damage, phosphorylated SREBP1 is ubiquitinated by FBXW7, and its degradation results in reduced expression of lipogenic enzymes. (G) Peli1 ubiquitinates NBS1, a component of the MRN complex, which facilitates ATM recruitment to a DSB site and promotes HR. (H) In CD8⁺ TIL, Peli1 ubiquitinates mTORC1 inhibitor TSC1 at K63, resulting in downregulation of metabolic reprogramming and effector functions of CD8⁺ T cells.