The overall objective of this research is to better understand the contribution of somatic cell mutagenesis to the etiology of cancer. We propose to study the molecular mechanisms of somatic cell mutagenesis by characterizing the frequencies and spectra of DNA sequence changes arising in different tissues in transgenic mice. A major goal of this project is to establish a system for studying mutagenesis in animals. Our approach is to study mutations in recombinant vectors inserted into the genomic DNA of transgenic mice. These vectors will be """"""""rescued"""""""" from untreated and carcinogen-treated animals, and the mutations will be scored and sequenced following selection in E. coli. The frequencies and spectra of spontaneous mutations will first be determined in vectors rescued from untreated mice. Emphasis will be placed on comparing the relative rates of spontaneous mutagenesis in the major target tissues for carcinogenesis (liver, skin, lung, spleen, kidney and brain). These studies will provide a data base for comparisons with chemically-induced mutations and will assess the genetic fidelity of the techniques used in the production of transgenic animals. Finally, the mutagenicities of the hepatocarcinogenic alkylating agents, dimethylnitrosamine (DMN) and diethynitrosamine (DEN), will be examined. Comparisons of mutation frequencies and spectra in tissues with different carcinogen susceptibilities will help to identify carcinogenic DNA lesions and to determine if organotropism in carcinogenesis correlates with tissue-specific mutagenesis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Chemical Pathology Study Section (CPA)
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Rutgers University
Schools of Pharmacy
New Brunswick
United States
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Ji, X; Klarmann, G J; Preston, B D (1996) Effect of human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein on HIV-1 reverse transcriptase activity in vitro. Biochemistry 35:132-43
Preston, B D (1996) Error-prone retrotransposition: rime of the ancient mutators. Proc Natl Acad Sci U S A 93:7427-31
Patel, P H; Preston, B D (1994) Marked infidelity of human immunodeficiency virus type 1 reverse transcriptase at RNA and DNA template ends. Proc Natl Acad Sci U S A 91:549-53
Klarmann, G J; Schauber, C A; Preston, B D (1993) Template-directed pausing of DNA synthesis by HIV-1 reverse transcriptase during polymerization of HIV-1 sequences in vitro. J Biol Chem 268:9793-802
Varela-Echavarria, A; Garvey, N; Preston, B D et al. (1992) Comparison of Moloney murine leukemia virus mutation rate with the fidelity of its reverse transcriptase in vitro. J Biol Chem 267:24681-8
Preston, B D; Doshi, R (1991) Molecular targets of chemical mutagens. Adv Exp Med Biol 283:193-209
Cheng, K C; Preston, B D; Cahill, D S et al. (1991) The vinyl chloride DNA derivative N2,3-ethenoguanine produces G----A transitions in Escherichia coli. Proc Natl Acad Sci U S A 88:9974-8
McBride, T J; Preston, B D; Loeb, L A (1991) Mutagenic spectrum resulting from DNA damage by oxygen radicals. Biochemistry 30:207-13