TAILIEUCHUNG - Báo cáo khoa học: In vitro expansion of DNA triplet repeats with bulge binders and different DNA polymerases

The expansion of DNA repeat sequences is associated with many genetic diseases in humans. Simple bulge DNA structures have been implicated as intermediates in DNA slippage within the DNA repeat regions. To probe the possible role of bulged structures in DNA slippage, we designed and synthesized a pair of simple chiral spirocyclic compounds [Xi Z, Ouyang D & Mu HT (2006)Bioorg Med Chem Lett16, 1180–1184], | ễFEBS Journal In vitro expansion of DNA triplet repeats with bulge binders and different DNA polymerases Di Ouyang Long Yi Liangliang Liu Hong-Tao Mu and Zhen Xi State Key Laboratory of Elemento-Organic Chemistry and Department of ChemicalBiology Nankai University Tianjin China Keywords bulge binder DNA polymerase DNA slippage drug-DNA interaction repeat sequences Correspondence Z. Xi State Key Laboratory of Elemento-Organic Chemistry and Department of ChemicalBiology Nankai University Tianjin 300071 China Fax 86 022 2350 4782 Tel 86 022 2350 4782 E-mail zhenxi@ Received 11 May 2008 revised 8 July 2008 accepted 10 July 2008 The expansion of DNA repeat sequences is associated with many genetic diseases in humans. Simple bulge DNA structures have been implicated as intermediates in DNA slippage within the DNA repeat regions. To probe the possible role of bulged structures in DNA slippage we designed and synthesized a pair of simple chiral spirocyclic compounds Xi Z Ouyang D Mu HT 2006 Bioorg Med Chem Lett 16 1180-1184 DDI-1A and DDI-1B which mimic the molecular architecture of the enediyne antitumor antibiotic neocarzinostatin chromophore. Both compounds strongly stimulated slippage in various DNA repeats in vitro. Enhanced slippage synthesis was found to be synchronous for primer and template. CD spectra and UV thermal stability studies supported the idea that DDI-1A and DDI-1B exhibited selective binding to the DNA bulge and induced a significant conformational change in bulge DNA. The proposed mechanism for the observed in vitro expansion of long DNA is discussed. doi Triplet repeats are the most abundant simple sequence repeats in the coding and non-coding sequences of all known eukaryotic genomes 1 . The frequency of specific types of triplet repeats and their localization in genes vary significantly between genomes reflecting their important role in genome evolution 1 2 . Expansions of DNA triplet repeat sequences .

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