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 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.
Ouyang
Di
D
State Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, Nankai University, Tianjin, China.
Yi
Long
L
Liu
Liangliang
L
Mu
Hong-Tao
HT
Xi
Zhen
Z
D004247:DNA / Q000096:biosynthesis / Q000737:chemistry* / Q000187:drug effects; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D005944:Glucosamine / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D009690:Nucleic Acid Conformation; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology*; D013698:Templates, Genetic; D019680:Trinucleotide Repeat Expansion / Q000187:drug effects*
D013141:Spiro Compounds; D004247:DNA; D004259:DNA-Directed DNA Polymerase; D005944:Glucosamine