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

Shahd Fouad,Mark A Hill,Owen S Wells,Vincenzo D’Angiolella

doi:10.3389/fphys.2019.01144

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.

Highlights

THE CULLIN RING UBIQUITIN LIGASESUbiquitylation is a versatile post-translational modification to control protein levels in cells and modulate cellular states to allow adaptation under stress
Given the specific roles of E3 ligase adaptors in regulating multiple aspects of the cellular responses to ionizing radiation (IR), it is possible to envision that alteration of the cullin-RING ligase (CRL) could be exploited to improve radiotherapy response in cancer cells
The development of proteolysis-targeting chimera (PROTAC) targeting CRL adaptors in the DNA damage could lead to drugs that are only activated upon IR or under a specific stimulus like hypoxia

Summary

Introduction

THE CULLIN RING UBIQUITIN LIGASESUbiquitylation is a versatile post-translational modification to control protein levels in cells and modulate cellular states to allow adaptation under stress. 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. The control of Cdc25A by β-TrCP following DNA damage is crucial for normal cell cycle progression and the checkpoint response.

Results

Conclusion