Xingzhi Tan

Stony Brook University, Stony Brook, New York, United States

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Publications (4)18.48 Total impact

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    ABSTRACT: 2-Acetylaminonaphthalene (2-AAN) has been recognized as a urinary bladder carcinogen in humans. The deacetylated form, 2-aminonaphthalene (2-AN), is metabolized in vivo and reacts primarily with guanine residues in DNA, resulting in the formation of dG-N(2)-aminonaphthalene (dG-N(2)-AN) adduct. Phosphoramidite chemical procedure has recently been established in our laboratory to prepare oligodeoxynucleotides containing a single dG-N(2)-acetylaminonaphthalene (dG-N(2)-AAN) adduct. Oligodeoxynucleotides ((5')TCCTCCTNXCCTCTC, where X is dG or dG-N(2)-AAN and N is C, A, T or G) with different bases 5' flanking to the lesion were prepared and were inserted into a single-strand shuttle vectors and used to establish the mutational frequency and specificity of dG-N(2)-AAN adduct in simian kidney cells. dG-N(2)-AAN adduct promoted preferential incorporation of dCMP, the correct base, opposite the lesion. When the 5' flanking base to the lesion was C, A or T, the mutational frequency was under 2.1%. When G flanked to the lesion, the mutational frequency was slightly increased to 4.2%. Misincorporation of dAMP, dTMP, and/or dGMP varied depending on the 5' flanking base. When dG-N(2)-AAN was positioned at codon 61 of noncoding strand of human c-Ha-ras1 gene ((5')TCCTCCTXGCCTCTC, where X is dG-N(2)-AAN), the mutational frequency was 6.7%; G-->T transversions (4.7%), followed by G-->A transition (2.0%), were observed. These results demonstrated that dG-N(2)-AAN is a weak mutagenic lesion in mammalian cells. The influence of 5' flanking sequence context was observed on the mutational frequency and specificity of this adduct.
    Chemico-Biological Interactions 04/2005; 152(2-3):131-8. DOI:10.1016/j.cbi.2005.02.005 · 2.98 Impact Factor
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    ABSTRACT: Comparative mutagenesis studies of N-(2'-deoxyguanosin-8-yl)-2-acetylaminofluorene (dG-AAF) and N-(2'-deoxyguanosin-8-yl)-2-aminofluorene (dG-AF) adducts positioned in the Nar I restriction enzyme site were performed using Escherichia coli (E. coli) and simian kidney (COS-7) cells. Oligodeoxynucleotides ((5)(')TCCTCG(1)G(2)CG(3)CCTCTC) containing a recognition sequence for the Nar I restriction enzyme were modified site-specifically with dG-AAF or dG-AF. Modified and unmodified oligomers inserted into single-stranded phagemid shuttle vectors were used to transform E. coli or to transfect COS-7 cells. Following replication in host cells, progeny plasmids were recovered and analyzed for mutations. In SOS-induced E. coli, dG-AAF primarily induced one- and two-base deletions. The mutational frequency varied, depending on the position modified in the Nar I site; 91% two-base deletions were observed at G(3), while 8.4% and 2.8% deletions were detected at G(2) and G(1), respectively. In contrast, dG-AF at any position in the Nar I site failed to produce deletions, generating primarily G --> T transversions (mutational frequency, 7.6-8.4%). In COS-7 cells, both dG-AAF and dG-AF primarily induced G --> T transversions. Mutation frequencies for dG-AAF were 9.4-24%, the highest values being at G(1) and G(3). Mutation frequencies for dG-AF were 9.3-21%, the higher value at G(2). We conclude from this study that the mutation potential of dG-AAF and dG-AF depends on the structure of the adduct, the sequence context of the lesion, and the host cell used for the experiment.
    Biochemistry 12/2002; 41(48):14255-62. DOI:10.1021/bi0202878 · 3.19 Impact Factor
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    ABSTRACT: Site-specifically modified oligodeoxynucleotides were used to explore the influence of neighboring base sequence context on the mutagenic potential of N-(deoxyguanosin-8-yl)-2-acetylaminofluorene (dG-AAF) and N-(deoxyguanosin-8-yl)-2-aminofluorene (dG-AF) in mammalian cells. Oligodeoxynucleotides ((5)(')TCCTCCTNXNCTCTC, where X is dG-AAF, dG-AF, or dG and N is C, A, G, or T) with different bases flanking the lesion were incorporated into a single-strand shuttle plasmid vector and used to establish the mutational frequency and specificity of dG-AAF and dG-AF adducts in simian kidney (COS-7) cells. Vectors containing dG-AAF promote preferential incorporation of dCMP at the site of the lesion; misincorporation of dAMP and dTMP also was observed. Mutational frequencies range from 11 to 23%. High mutational frequencies (18-23%) were observed when G or T was positioned 5' to dG-AAF and a lower frequency (11%) when C was 5' to the lesion. dCMP was predominantly incorporated opposite the dG-AF adduct when C, A, or T was 5' to the lesion; dAMP and dTMP were misincorporated at a frequency of 2-4%. With G 5' to the lesion, the overall mutational frequency for dG-AF ranged between 11 and 70%; the highest value occurred when C was the 3' flanking base, and the predominant mutation event was G --> T transversion (59%). We conclude from these experiments that dG-AAF and dG-AF promote G --> T transversions and G --> A transitions in mammalian cells. The mutational frequency and specificity of dG-AF vary significantly, depending on the nature of the bases flanking the lesion.
    Biochemistry 04/2001; 40(12):3717-22. DOI:10.1021/bi0027581 · 3.19 Impact Factor
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    ABSTRACT: The DNA adduct 8-amino-24-deoxyguanosine (8-amino-dG) is found in liver DNA of rats treated with the hepatocarcinogen 2-nitropropane. Site-specifi- cally modified oligodeoxynucleotides were used to explore the mutagenic potential of 8-amino-dG in simian kidney (COS-7) cells. Oligodeoxynucleotides (54-TCCTCCTX1G2CCTCTC and 54-TCCTCCTG1X2CC- TCTC, X = dG or 8-amino-dG) with the lesion positioned at codon 60 or 61 of the non-coding strand of the human c-Ha-ras1 gene were inserted into single- stranded phagemid vectors and transfected into COS-7 cells. The progeny plasmid obtained was used to transform Escherichia coli DH10B. Transformants were analyzed by oligodeoxynucleotide hybridization and DNA sequencing to establish the mutation fre- quency and spectrum produced by the modified base. The correct base, dCMP, was incorporated preferen- tially opposite 8-amino-dG at X1 and X2. When 8-amino- dG was at X1, targeted GNH2∀ T transversions were detected, along with smaller numbers of GNH2∀ A transitions and GNH2∀ C transversions. When the adduct was at X2, only GNH2∀ T transversions were observed. The frequencies of targeted mutation at X1 and X2 were 2.7 and 1.7%, respectively. Mutation frequency and mutagenic spectrum were sequence context dependent. In addition, non-targeted G∀ T transversions, accompanied by some G∀ A trans- itions, were detected 54 to 8-amino-dG when the lesion was at X2. We conclude that 8-amino-dG is a mutagenic lesion, generating G∀ T and G∀ C transversions and G∀ A transitions in mammalian cells.
    Nucleic Acids Research 06/1999; 27(11). DOI:10.1093/nar/27.11.2310 · 9.11 Impact Factor