Cullin Ring Ubiquitin Ligases (CRLs) in Cancer: Responses to Ionizing Radiation (IR) Treatment

Abstract

Treatment with ionizing radiation (IR) remains the cornerstone of therapy for multiple cancer types, including disseminated and aggressive diseases in the palliative setting. Radiotherapy efficacy could be improved in combination with drugs that regulate the ubiquitin-proteasome system (UPS), many of which are currently being tested in clinical trials. The UPS operates through the covalent attachment of ATP-activated ubiquitin molecules onto substrates following the transfer of ubiquitin from an E1, to an E2, and then to the substrate via an E3 enzyme. The specificity of ubiquitin ligation is dictated by E3 ligases, which select substrates to be ubiquitylated. Among the E3s, cullin ring ubiquitin ligases (CRLs) represent prototypical multi-subunit E3s, which use the cullin subunit as a central assembling scaffold. CRLs have crucial roles in controlling the cell cycle, hypoxia signaling, reactive oxygen species clearance and DNA repair; pivotal factors regulating the cancer and normal tissue response to IR. Here, we summarize the findings on the involvement of CRLs in the response of cancer cells to IR, and we discuss the therapeutic approaches to target the CRLs which could be exploited in the clinic.

A Comprehensive Proteomics Analysis of the JC Virus (JCV) Large and Small Tumor Antigen Interacting Proteins: Large T Primarily Targets the Host Protein Complexes with V-ATPase and Ubiquitin Ligase Activities While Small t Mostly Associates with Those Having Phosphatase and Chromatin-Remodeling Functions

“…Ubiquitination is a post-translational modification of proteins, carried out by the sequential activity of a group of ligases, including ubiquitin-activating (E1), ubiquitin-conjugating (E2), and ubiquitin-ligating (E3) enzymes, on the specific lysine residues of the target substrates [ 114 ]. The human genome encodes two E1, ~35 E2, and >700 E3 ubiquitin ligases [ 115 ] and ubiquitination is primarily known for the degradation of protein substrates upon the modification. However, in recent years, this post-translational modification has emerged as a critical mechanism by which it appears to regulate diverse biological processes, including various aspects of immune function and signaling pathways [ 116 , 117 ].…”

Ubiquitomics: An Overview and Future

“…A 2012 study exploring coevolution of PTM sites within proteins showed that ubiquitination sites frequently coevolve with phosphorylation and acetylation sites [ 39 ]. For example, phosphorylation of protein such as cyclins during the cell cycle recruits cullin-RING E3 ligases, leading to cyclin degradation by the proteasome [ 40 ]. However, this analysis only employed 600 ubiquitination sites, so new investigations with deeper ubiquitome data may show new trends.…”

Regulation of NFκB Signalling by Ubiquitination: A Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma?

“…As mention previously, MLN4924 can impact the function of the CRL sub-family of E3 ligases. CRLs play a critical role in NFκB activation [ 147 ]. The SCF E3 ligase complex containing CUL1 is the most well characterized to date.…”