The interplay between DNA topoisomerase 2α post-translational modifications and drug resistance.

Christophe Lotz,Valérie Lamour

doi:10.20517/cdr.2019.114

Abstract

The type 2 DNA topoisomerases (Top2) are conserved enzymes and biomarkers for cell proliferation. The catalytic activities of the human isoform Top2α are essential for the regulation of DNA topology during DNA replication, transcription, and chromosome segregation. Top2α is a prominent target for anti-cancer drugs and is highly regulated by post-translational modifications (PTM). Despite an increasing number of proteomic studies, the extent of PTM in cancer cells and its importance in drug response remains largely uncharacterized. In this review, we highlight the different modifications affecting the human Top2α in healthy and cancer cells, taking advantage of the structure-function information accumulated in the past decades. We also overview the regulation of Top2α by PTM, the level of PTM in cancer cells, and the resistance to therapeutic compounds targeting the Top2 enzyme. Altogether, this review underlines the importance of future studies addressing more systematically the interplay between PTM and Top2 drug resistance.

Highlights

The type 2 DNA topoisomerases (Top2) are evolutionary conserved enzymes and biomarkers for cell proliferation[1]
Cancer cells may develop resistance that can be attributed to Top2 single point mutations, alteration of gene expression, or regulation of post-translational modifications (PTM)[10]
Most phosphorylations were found in the C-terminal domain (CTD) of the Top2a isoform, related to its role in the cell cycle

Summary

INTRODUCTION

The type 2 DNA topoisomerases (Top2) are evolutionary conserved enzymes and biomarkers for cell proliferation[1]. Lys1196 was found to be a site for acetylation in Jurkat cells, ubiquitination in Jurkat and HEP-2 cells, and SUMOylation in HeLa cells[43,46,47] This residue is located in a hinge region between the C-gate domain and the CTD and could be involved in the regulation of Top activities [Figure 3B]. Lys378 is ubiquitinated by the E3 ligase activity of the APC/C complex, promoting 26S proteasome degradation at G1 phase, modulating Top2a levels for chromosome maintenance[52] This residue interacts directly with the ATP molecule and could be accessible to modifications when the N-gate is open during the catalytic cycle. No drug resistant mutations targeting known PTM sites could be found in the literature except for vosaroxin resistant yeast cells[72], it cannot be excluded that such events occur in the Top2a gene of resistant

CONCLUSION

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