Xingzhi Tan

Stony Brook University, Stony Brook, NY, United States

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Publications (5)24.16 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. · 2.97 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. · 3.38 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. · 3.38 Impact Factor
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    ABSTRACT: The comparative mutagenicity of 8-oxo-7,8-dihydro-2'-deoxyadenosine (8-oxodA) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) was explored using simian kidney (COS-7) cells. Oligodeoxynucleotides ¿5'-TCCTCCT- G(1)X(2)CCTCTC or 5'-TCCTCCTX(1)G(2)CCTCTC (X = dA, dG, 8-oxodA or 8-oxodG) containing 8-oxodA or 8-oxodG positioned within codon 60 or 61 of the non-coding strand of human c-Ha-ras1 gene were inserted into a single-stranded phagemid shuttle vector. The vector was replicated in COS-7 cells and the progeny plasmids were used to transform Escherichia coli DH10B. The transformants were analyzed by oligodeoxynucleotide hybridization and DNA sequence analysis to establish the mutation frequency and specificity. When 8-oxodA was positioned at X(1), targeted A(oxo)-->C transversions were detected; the mutation frequency was 1.2%. When 8-oxodA was positioned at X(2), one targeted mutant among 416 colonies screened (an A(oxo)-->G transition) was detected. Thus, the mutation frequency and spectrum of 8-oxodA depend on the sequence context of the lesion. The mutation frequency of 8-oxodG at X(1) and X(2) was 5.2 and 6.8%, respectively. G(oxo)-->T transversions dominated the spectrum, accompanied by small numbers of G(oxo)-->A transitions and G(oxo)-->C transversions. We conclude that 8-oxodA has mutagenic potential in mammalian cells, generating A-->C transversions. However, when tested under similar conditions, the mutation frequency of 8-oxodA is at least four times lower than that of 8-oxodG.
    Carcinogenesis 01/2000; 20(12):2287-92. · 5.64 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; · 8.81 Impact Factor