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DNA curvature at A tracts containing a non-polar thymine mimic.

ABSTRACT: We report the first experimental probing of electrostatic interactions on the pyrimidine side of a bent A tract. Although the curvature of short A tracts (A4-A6) has long been studied, its physical origins remain under debate. Current hypotheses include the influence of major-groove hydrogen bonds between propeller-twisted base pairs, electrostatic effects of closely associated minor-groove cations, effects of minor-groove solvation, and stacking effects at the junctions adjacent to the A tract. We investigated this problem through the substitution of thymidines in A5 tracts by difluorotoluene deoxynucleoside (F), a non-polar molecule of the same size and shape which lacks hydrogen bonding and metal-ion complexing capabilities. Ligation experiments with phased A tracts demonstrated that F substitution has asymmetric effects on the bend angle. The strongest effects occurred at the second and third thymines where curvature was reduced from 19.8 degrees to 5.3 degrees and 9.6 degrees, respectively. Moderate effects were observed with substitutions at positions 1 and 4, while substitution at position 5 had no effect on bend angle. The results support the hypothesis that highly localized electrostatic interactions are a principal cause of A-tract curvature. Furthermore, they are most consistent with the notion that local metal-ion complexation at O2 of thymine is a strong component of these interactions.

SUBMITTER: Maki A

PROVIDER: S-EPMC149194 | biostudies-literature | 2003 Feb

REPOSITORIES: biostudies-literature

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DNA curvature at A tracts containing a non-polar thymine mimic.

Maki Angèle A Brownewell Floyd E FE Liu Dongyu D Kool Eric T ET

Nucleic acids research 20030201 3

We report the first experimental probing of electrostatic interactions on the pyrimidine side of a bent A tract. Although the curvature of short A tracts (A4-A6) has long been studied, its physical origins remain under debate. Current hypotheses include the influence of major-groove hydrogen bonds between propeller-twisted base pairs, electrostatic effects of closely associated minor-groove cations, effects of minor-groove solvation, and stacking effects at the junctions adjacent to the A tract. ...[more]

PMID: 12560504

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Project description:Background/objectiveLicorice has been shown to possess cancer chemopreventive effects. However, glycyrrhizin, a major component in licorice, was found to interfere with steroid metabolism and cause edema and hypertension. The roasting process of licorice modifies the chemical composition and converts glycyrrhizin to glycyrrhetinic acid. The purpose of this study was to examine the anti-carcinogenic effects of the ethanol extract of roasted licorice (EERL) and to identify the active compound in EERL.Materials/methodsEthanol and aqueous extracts of roasted and un-roasted licorice were prepared. The active fraction was separated from the methylene chloride (MC)-soluble fraction of EERL and the structure of the purified compound was determined by nuclear magnetic resonance spectroscopy. The anti-carcinogenic effects of licorice extracts and licochalcone A was evaluated using a MTT assay, Western blot, flow cytometry, and two-stage skin carcinogenesis model.ResultsEERL was determined to be more potent and efficacious than the ethanol extract of un-roasted licorice in inhibiting the growth of DU145 and MLL prostate cancer cells, as well as HT-29 colon cancer cells. The aqueous extracts of un-roasted and roasted licorice showed minimal effects on cell growth. EERL potently inhibited growth of MCF-7 and MDA-MB-231 breast, B16-F10 melanoma, and A375 and A2058 skin cancer cells, whereas EERL slightly stimulated the growth of normal IEC-6 intestinal epithelial cells and CCD118SK fibroblasts. The MC-soluble fraction was more efficacious than EERL in inhibiting DU145 cell growth. Licochalcone A was isolated from the MC fraction and identified as the active compound of EERL. Both EERL and licochalcone A induced apoptosis of DU145 cells. EERL potently inhibited chemically-induced skin papilloma formation in mice.ConclusionsNon-polar compounds in EERL exert potent anti-carcinogenic effects, and that roasted rather than un-roasted licorice should be favored as a cancer preventive agent, whether being used as an additive to food or medicine preparations.

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DNA curvature at A tracts containing a non-polar thymine mimic.

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DNA curvature at A tracts containing a non-polar thymine mimic.

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