Fengting Liang

University of Rhode Island, Kingston, Rhode Island, United States

Are you Fengting Liang?

Claim your profile

Publications (7)39.72 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The environmental arylamine mutagens are implicated in the etiology of various sporadic human cancers. Arylamine-modified dG lesions were studied in two fully paired 11-mer duplexes with a -G*CN- sequence context, in which G* is a C8-substituted dG adduct derived from fluorinated analogs of 4-aminobiphenyl (FABP), 2-aminofluorene (FAF) or 2-acetylaminofluorene (FAAF), and N is either dA or dT. The FABP and FAF lesions exist in a simple mixture of 'stacked' (S) and 'B-type' (B) conformers, whereas the N-acetylated FAAF also samples a 'wedge' (W) conformer. FAAF is repaired three to four times more efficiently than FABP and FAF. A simple A- to -T polarity swap in the G*CA/G*CT transition produced a dramatic increase in syn-conformation and resulted in 2- to 3-fold lower nucleotide excision repair (NER) efficiencies in Escherichia coli. These results indicate that lesion-induced DNA bending/thermodynamic destabilization is an important DNA damage recognition factor, more so than the local S/B-conformational heterogeneity that was observed previously for FAF and FAAF in certain sequence contexts. This work represents a novel 3'-next flanking sequence effect as a unique NER factor for bulky arylamine lesions in E. coli.
    Nucleic Acids Research 11/2012; · 8.81 Impact Factor
  • Fengting Liang, Bongsup P Cho
    [Show abstract] [Hide abstract]
    ABSTRACT: We report a systematic spectroscopic investigation on the conformational evolution during primer extension of a bulky fluoroaminofluorene-modified dG adduct (FAF-dG) in chemically simulated translesion synthesis. FAF-dG was paired either with dC or dA (dC-match and dA-mismatch series, respectively). Dynamic (19)F NMR/CD results showed that the FAF-adduct exists in a syn/anti equilibrium and that its conformational characteristics are modulated by the identity of an inserted nucleotide at the lesion site and the extent of primer elongation. At the pre-insertion site, the adduct adopted preferentially a syn conformation where FAF stacked with preceding bases. Insertion of the correct nucleotide dC at the lesion site and subsequent elongation resulted in a gradual transition to the anti conformation. By contrast, the syn conformer was persistent along with primer extension in the dA-mismatch series. In the dC-match series, FAF-induced thermal (T(m)) and thermodynamic (-ΔG°(37 °C)) stabilities were significantly reduced relative to those of the controls. However, the corresponding T(m) and -ΔG°(37 °C) values were increased in the FAF-modified mismatched dA series. The lesion impact persisted up to three 5'-nucleotides from the lesion. Occupation of the minor groove of the W-conformer with the bulky carcinogenic fluorene moiety not only would limit the DNA mobility but also would impose a serious difficulty for the active site of a polymerase throughout the replication process. Our spectroscopic results are consistent with reported data on AF, which showed dramatic (~10(4)-fold) differences in the nucleotide insertion rates between the dC-match and dA-mismatch series. The results emphasize the importance of adduct-induced steric constraints for determining the replication fidelity of a polymerase.
    Chemical Research in Toxicology 03/2011; 24(4):597-605. · 3.67 Impact Factor
  • Source
    Fengting Liang, Bongsup P Cho
    [Show abstract] [Hide abstract]
    ABSTRACT: DNA damage by adduct formation is a critical step for the initiation of carcinogenesis. Aromatic amines are strong inducers of environmental carcinogenesis. Their DNA adducts are known to exist in an equilibrium between the major groove (B) and base-displaced stacked (S) conformations. However, the factors governing such heterogeneity remain unclear. Here we conducted extensive calorimetry/NMR/CD studies on the model DNA lesions caused by fluorinated 2-aminfluorene (FAF) and 4-aminobiphenyl (FABP) in order to gain thermodynamic and kinetic insights into the S/B conformational equilibrium. We demonstrate that there are large differences in enthalpy-entropy compensations for FABP and FAF. The small and flexible FABP exclusively adopts the less perturbed B conformer with small enthalpy (DeltaDeltaH-2.7 kcal/mol)/entropy (DeltaDeltaS-0.7 eu) change. In contrast, FAF stacks better and exists as a mixture of B and S conformers with large enthalpy (DeltaDeltaH-13.4 kcal/mol)/entropy (DeltaDeltaS-34.2 eu) compensation. van't Hoff analysis of dynamic (19)F NMR data indicated DeltaH(B<-->S) = 4.1 kcal/mol in favor of the B conformer and DeltaS(B<-->S) = 15.6 cal mol(-1) K(-1) in favor of the intercalated S conformer. These findings demonstrate that the favorable entropy of the S conformer over B conformer determines the S/B population ratios at physiological temperatures.
    Biochemistry 12/2009; 49(2):259-66. · 3.38 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We report synthesis and characterization of a complete set of alpha,beta-methylene-2'-dNTPs (alpha,beta-m-dNTP; N = A, C, T, G, 12-15) in which the alpha,beta-oxygen linkage of natural dNTP was replaced by a methylene group. These nucleotides were designed to be noncleavable substrates for DNA polymerases. Synthesis entails preparation of 2'-deoxynucleoside 5'-diphosphate precursors, followed by an enzymatic gamma-phosphorylation. All four synthesized alpha,beta-m-dNTPs were found to be potent inhibitors of polymerase beta, with K i values ranging 1-5 microM. During preparation of the dG and dT derivatives of alpha,beta-methylene diphosphate, we also isolated significant amounts of 3,5'-cyclo-dG (16) and 2,5'-cyclo-dT (17), respectively. These novel 2'-deoxycyclonucleosides were formed via a base-catalyzed intramolecular cyclization (N3 --> C5' and O2 --> C5', respectively). In acidic solution, both 16 and 17 underwent glycolysis, followed by complete depurination. When exposed to alkaline conditions, 16 underwent an oxidative deamination to produce 3,5'- cyclo-2'-deoxyxanthosine (19), whereas 17 was hydrolyzed exclusively to dT.
    Journal of Medicinal Chemistry 09/2008; 51(20):6460-70. · 5.61 Impact Factor
  • Source
    Fengting Liang, Bongsup P Cho
    Journal of the American Chemical Society 11/2007; 129(40):12108-9. · 10.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Adduct-induced conformational heterogeneity complicates the understanding of how DNA adducts exert mutation. A case in point is the N-deacetylated AF lesion [N-(2'-deoxyguanosin-8-yl)-2-aminofluorene], the major adduct derived from the strong liver carcinogen N-acetyl-2-aminofluorene. Three conformational families have been previously characterized and are dependent on the positioning of the aminofluorene rings: B is in the "B-DNA" major groove, S is "stacked" into the helix with base-displacement, and W is "wedged" into the minor groove. Here, we conducted (19)F NMR, CD, T(m), and modeling experiments at various primer positions with respect to a template modified by a fluorine tagged AF-adduct (FAF). In the first set, the FAF-G was paired with C and in the second set it was paired with A. The FAF-G:C oligonucleotides were found to preferentially adopt the B or S-conformers while the FAF-G:A mismatch ones preferred the B and W-conformers. The conformational preferences of both series were dependent on temperature and complementary strand length; the largest differences in conformation were displayed at lower temperatures. The CD and T(m) results are in general agreement with the NMR data. Molecular modeling indicated that the aminofluorene moiety in the minor groove of the W-conformer would impose a steric clash with the tight-packing amino acid residues on the DNA binding area of the Bacillus fragment (BF), a replicative DNA polymerase. In the case of the B-type conformer, the carcinogenic moiety resides in the solvent-exposed major groove throughout the replication/translocation process. The present dynamic NMR results, combined with previous primer extension kinetic data by Miller & Grollman, support a model in which adduct-induced conformational heterogeneities at positions remote from the replication fork affect polymerase function through a long-range DNA-protein interaction.
    Journal of Molecular Biology 03/2007; 366(5):1387-400. · 3.91 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We report novel induced circular dichroism (ICD) characteristics for probing the conformational heterogeneity induced by the arylamine carcinogen 2-aminofluorene, namely, B type (B), stacked (S), and wedged (W) conformers. CD experiments were conducted with five different aminofluorene-modified DNA duplexes (I-V). An intense positive ICD was observed for the W conformeric I in the 290-360 nm range (ICD(290)(-)(360nm)). This was in contrast to the negative ICD(290)(-)(360nm) exhibited by the mostly B conformeric V (17% S/83% B). Duplex IV, which adopts an approximately equal mixture of S (53%) and B (47%), exhibited low ellipticities along the baseline. The magnitude of the positive ICD for I was significantly greater than that observed for II (70% S/30% B). While the ICD(290)(-)(360nm) of the W conformeric III showed no changes in intensity with increasing temperature from 10 to 35 degrees C, dramatic changes were observed for I across the same temperature range. Dynamic (19)F NMR results revealed that I exists in an 85:15 mixture of W and S/B conformers. The dramatic intensity changes observed for I are consistent with the presence of a W/B heterogeneity because of its susceptibility to result in a large difference on the magnitude of the ICD(290)(-)(360nm). In conclusion, the sign and magnitude of the ICD(290)(-)(360)(nm) are sensitive conformational markers for studying arylamine-induced conformational heterogeneity. The temperature-dependent ICD(290)(-)(360nm) data, coupled with (19)F NMR spectroscopy, provide valuable information about conformational distribution and dynamics, which are important factors that affect mutational outcomes.
    Chemical Research in Toxicology 09/2006; 19(8):1040-3. · 3.67 Impact Factor