A model for triple helix formation on human telomerase reverse transcriptase (hTERT) promoter and stabilization by specific interactions with the water soluble perylene derivative, DAPER

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• 作者：Luigi Rossetti ; Giuliana D'Isa ; Clementina Mauriello ; Michela Varra ; Pasquale De Santis ; Luciano Mayol ; Maria Savino
• 关键词：DNA triple helix ; Triplex forming oligonucleotide ; Telomerase inhibition ; hTERT promoter ; Perylene derivative DAPER ; Triplex and duplex– ; DAPER complexes
• 刊名：Biophysical Chemistry
• 出版年：2007
• 期刊代码：11_03014622
• 类别：ch
• 出版时间：August 2007
• 卷：129
• 期：1
• 页码：70-81
• 文件大小：1368 K

摘要

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′-(dimethylamino) 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.