Resveratrol: A novel type of topoisomerase II inhibitor

J Biol Chem. 2017 Dec 22;292(51):21011-21022. doi: 10.1074/jbc.M117.810580. Epub 2017 Oct 26.

Abstract

Resveratrol, a polyphenol found in various plant sources, has gained attention as a possible agent responsible for the purported health benefits of certain foods, such as red wine. Despite annual multi-million dollar market sales as a nutriceutical, there is little consensus about the physiological roles of resveratrol. One suggested molecular target of resveratrol is eukaryotic topoisomerase II (topo II), an enzyme essential for chromosome segregation and DNA supercoiling homeostasis. Interestingly, resveratrol is chemically similar to ICRF-187, a clinically approved chemotherapeutic that stabilizes an ATP-dependent dimerization interface in topo II to block enzyme activity. Based on this similarity, we hypothesized that resveratrol may antagonize topo II by a similar mechanism. Using a variety of biochemical assays, we find that resveratrol indeed acts through the ICRF-187 binding locus, but that it inhibits topo II by preventing ATPase domain dimerization rather than stabilizing it. This work presents the first comprehensive analysis of the biochemical effects of both ICRF-187 and resveratrol on the human isoforms of topo II, and reveals a new mode for the allosteric regulation of topo II through modulation of ATPase status. Natural polyphenols related to resveratrol that have been shown to impact topo II function may operate in a similar manner.

Keywords: DNA topoisomerase; conformational change; enzyme inhibitor; inhibition mechanism; protein drug interaction; resveratrol; site-directed mutagenesis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphatases / antagonists & inhibitors
  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / metabolism
  • Allosteric Regulation
  • Amino Acid Substitution
  • DNA Topoisomerases, Type II / chemistry
  • DNA Topoisomerases, Type II / genetics
  • DNA Topoisomerases, Type II / metabolism
  • Dexrazoxane / chemistry
  • Dexrazoxane / pharmacology
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Mutagenesis, Site-Directed
  • Poly-ADP-Ribose Binding Proteins / antagonists & inhibitors
  • Poly-ADP-Ribose Binding Proteins / chemistry
  • Poly-ADP-Ribose Binding Proteins / metabolism
  • Protein Interaction Domains and Motifs / drug effects
  • Protein Multimerization / drug effects
  • Resveratrol / chemistry
  • Resveratrol / pharmacology*
  • Saccharomyces cerevisiae Proteins / antagonists & inhibitors
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / metabolism
  • Topoisomerase II Inhibitors / chemistry
  • Topoisomerase II Inhibitors / pharmacology*

Substances

  • Poly-ADP-Ribose Binding Proteins
  • Saccharomyces cerevisiae Proteins
  • Topoisomerase II Inhibitors
  • Dexrazoxane
  • Adenosine Triphosphatases
  • DNA Topoisomerases, Type II
  • TOP2A protein, human
  • TOP2B protein, human
  • Resveratrol

Associated data

  • PDB/4GFH
  • PDB/1QZR