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.
Institute for Cellular and Molecular Biology and Division of Medicinal Chemistry and Drug Dynamics Institute, The University of Texas at Austin, 78712, USA.
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Bennett
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Hurley
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