NYMC Faculty Publications

Control of DNA Structure and Function by Phytochemicals/DNA Interaction: Resveratrol/Piceatannol Induces Cu

DOI

10.1016/j.freeradbiomed.2019.12.034

Journal Title

Free Radical Biology & Medicine

First Page

212

Last Page

219

Document Type

Article

Publication Date

2-1-2020

Department

Biochemistry and Molecular Biology

Abstract

Topoisomerases are enzymes that catalyze DNA unwinding and scissions to resolve topological entanglements possibly arising during DNA replication/transcription. Chemicals which disrupt or inhibit topoisomerase-mediated DNA unwinding can induce breaks that subsequently lead to programmed cell death. Herein we perform experiments guided by the following considerations. First, topoisomerase 1 initiates DNA cleavage utilizing the hydroxyl group of tyrosine 723 on its catalytic site as a nucleophile to attack the electrophilic phosphate on the DNA sugar-phosphate backbone. Secondly, the grape polyphenol resveratrol displays both topoisomerase inhibitory and Cu(2+)-dependent DNA-cutting activities, which contribute to its DNA replication/transcription inhibitory/anti-tumorigenic effects. Lastly, resveratrol contains a tyrosine-like phenolic ring; thus, upon binding to DNA whether resveratrol could act as a tyrosine mimetic to unwind and cut DNA via its hydroxyl groups warrants investigation. Polyphenol-DNA interactions (PDIs) were investigated using UV-visible spectral analysis; additionally, PDI mediated DNA changes were further analyzed by agarose gel electrophoresis using 3 supercoiled plasmid DNAs (pBR322, pSJ3, pHOT-1) as substrates. Resveratrol mediates time- and temperature-dependent, Cu(2+)- independent, non-enzymatic cleavage of supercoiled plasmid DNA into open, circular DNA products. Varying degree of unwinding of supercoiled DNA nucleolytic activity was also observed with other polyphenols including, piceatannol, quercetin, myricetin and EGCG. Interestingly, we found that piceatannol mediated Cu(2+)-independent DNA-cleavage activity was abolished by EDTA. The PDI-mediated nucleolytic cleavage of supercoiled DNA reported herein shows that polyphenolic phytochemicals display genome-active, nuclear effects by directly targeting the DNA topology which in turn could impact macromolecular processes associated with faithful replication and transmission of genetic information.

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