Inhibition of unwinding of G-quadruplex structures by Sgs1 helicase in the presence of N,N'-bis[2-(1-piperidino)ethyl]-3,4,9,10-perylenetetracarboxylic diimide, a G-quadruplex-interactive ligand.
N,N'-Bis[2-(1-piperidino)ethyl]-3,4,9,10-perylenetetracarboxylic diimide (PIPER), a perylene derivative, is a very potent and selective G-quadruplex DNA-interactive agent. It has been shown to inhibit DNA polymerase and telomerase by stacking externally to the G-tetrads in the G-quadruplex structures. Recently, we have demonstrated that this small molecule greatly accelerates the assembly of G-quadruplex structures in a cell-free system. In this report, we present data demonstrating that PIPER prevents the unwinding of G-quadruplex structures by yeast Sgs1 helicase. Sgs1 belongs to the RecQ DNA helicase family whose members include other G-quadruplex DNA unwinding helicases, such as human Bloom's syndrome and human Werner's syndrome helicases. PIPER specifically prevents the unwinding of G-quadruplex DNA but not duplex DNA by Sgs1. Competition experiments indicate that this inhibitory activity is due to the interaction of PIPER with G-quadruplex structures rather than the helicase itself. These results combined with previous studies suggest a possible mechanism of action for these G-quadruplex-interactive agents inside cells: they might induce G-quadruplex formation in G-rich regions on genomic DNA, stabilize these structures, and prevent them from being cleared by enzymes such as helicases. The G-quadruplex structures may, in turn, disrupt some critical cellular events such as DNA replication, transcription regulation, and telomere maintenance.
Han
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Institute for Cellular and Molecular Biology and Division of Medicinal Chemistry and Drug Dynamics Institute, The University of Texas at Austin, 78712, USA.
Bennett
R J
RJ
Hurley
L H
LH
D000873:Anthracenes / Q000737:chemistry*; D004247:DNA / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000302:isolation & purification; D004265:DNA Helicases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004277:DNA, Single-Stranded / Q000737:chemistry; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000737:chemistry*; D054856:G-Quadruplexes; D006147:Guanine / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D009690:Nucleic Acid Conformation / Q000187:drug effects*; D009692:Nucleic Acid Heteroduplexes / Q000037:antagonists & inhibitors / Q000737:chemistry; D010569:Perylene / Q000031:analogs & derivatives; D010880:Piperidines / Q000737:chemistry*; D053484:RecQ Helicases; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins
D000873:Anthracenes; D004277:DNA, Single-Stranded; D004791:Enzyme Inhibitors; D008024:Ligands; C116108:N,N'-bis(2-1(piperidino)-ethyl)-3,4,9,10-perylene-tetracarboxylic diimide; D009692:Nucleic Acid Heteroduplexes; D010880:Piperidines; D029701:Saccharomyces cerevisiae Proteins; D010569:Perylene; D006147:Guanine; D004247:DNA; C090472:SGS1 protein, S cerevisiae; D004265:DNA Helicases; D053484:RecQ Helicases