Journal
BIOPHYSICAL CHEMISTRY
Volume 129, Issue 1, Pages 70-81Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bpc.2007.05.009
Keywords
DNA triple helix; triplex forming oligonucleotide; telomerase inhibition; hTERT promoter; perylene derivative DAPER; triplex and duplex-DAPER complexes
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The promoter of human telomerase reverse transcriptase (hTERT) gene, in the region from - 1000 to + 1, contains two homopurine-homopyrimidine sequences (-835/-814 and -108/-90), that can be considered as potential targets to triple helix forming oligonucleotides (TFOs) for applying antigene strategy. We have chosen the sequence (-108/-90) on the basis of its unfavorable chromatin organization, evaluated by theoretical nucleosome positioning and nuclease hypersensitive sites mapping. On this sequence, anti-parallel triplex with satisfactory thermodynamic stability is formed by two TFOs, having different lengths. Triplex stability is significantly increased by specific interactions with the perylene derivative N,N'-bis[3,3'-(dimcthylamino) propylamine]3,4,9,10-perylenetetracarboxylic diimide (DAPER). Since DAPER is a symmetric molecule, the induced Circular Dichroism (CD) spectra in the range 400-600 nm allows us to obtain information on drug binding to triplex and duplex DNA. The drug-induced ellipticity is significantly higher in the case of triplex with respect to duplex and, surprisingly, it increases at decreasing of DNA. A model is proposed where self-stacked DAPER binds to triplex or to duplex narrow grooves. (c) 2007 Elsevier B.V. All rights reserved.
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