Effects of a halogenated G-quadruplex ligand from the pyridine dicarboxamide series on the terminal sequence of XpYp telomere in HT1080 cells.
Non-canonical four-stranded structures called G-quadruplexes can form among telomere repeats during its replication. Small molecule ligands able to interact and to stabilize G-quadruplexes were shown to disrupt the binding of essential telomeric components, such as POT1 and to trigger a telomeric dysfunction associated with a delayed growth arrest in tumor cells. We describe here the chemical synthesis and the G-quadruplex binding properties of three halogenated analogs of the 360A ligand that belongs to the 2,6 pyridine dicarboxamide series. 360A is now commonly used as a benchmark both for biophysical and cellular assays as this compound was shown to display a potent affinity and selectivity for telomeric G-quadruplex DNA over duplex DNA and to induce delayed growth inhibition in HT1080 tumor cell line. Two biophysical assays indicate that, in most cases, the presence of the halogen atom seems to slightly improve the interaction with the telomeric quadruplex. For stability reasons, the bromo derivative (360A-Br) was selected for the cellular assays. Since POT1 participates to the fine tuning of the C-strand end resection during telomere replication, we investigated the effect of 360A-Br to alter the terminal nucleotide composition of XpYp telomere in HT1080 cells using C-STELA. HT1080 cells treated for up to 24 days with 360A-Br presented some minor but significant variations of C-strand terminal nucleotide composition, also observed with a partial siRNA depletion of POT1. The relevance of these minor modifications of the telomeric C-strand resection induced by 360A-Br in HT1080 cells are discussed.
Structure des Acides Nucléiques, Télomères et Evolution, Inserm U565, CNRS UMR 7196, Muséum National d'Histoire Naturelle, 43 rue Cuvier, 75231 Paris cedex 05, France.
Assitan
A
Sidibe
Florian
F
Hamon
Eric
E
Largy
Dennis
D
Gomez
Marie-Paule
MP
Teulade-Fichou
Chantal
C
Trentesaux
Jean-François
JF
Riou
D001482:Base Composition / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D001966:Bromine / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D054856:G-Quadruplexes; D045325:HCT116 Cells; D054879:Halogenation; D006801:Humans; D008024:Ligands; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D034622:RNA Interference; D000089804:Shelterin Complex; D021241:Spectrometry, Mass, Electrospray Ionization; D016615:Telomere / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism
C502660:2,6-N,N'-methyl-quinolinio-3-yl-pyridine dicarboxamide; D008024:Ligands; C440849:POT1 protein, human; D011725:Pyridines; D011804:Quinolines; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D004247:DNA; D001966:Bromine