The role of adduct site-specific mutagenesis in understanding how carcinogen-DNA adducts cause mutations: perspective, prospects and problems.

Usually, a particular mutagen/carcinogen forms adducts at many sites in DNA, making it impossible to determine which type of adduct causes which mutation and why. Adduct site-specific mutagenesis studies, in which a single adduct is built into a vector, can be used to overcome this problem. The adduct can be situated in double-stranded DNA, single-stranded DNA or in a single-stranded gap, and the benefit and concerns associated with each are addressed. An adduct site-specific study is most useful when it is compared to a mutagenesis study with its corresponding mutagen/carcinogen. Mutations induced by a particular mutagen/carcinogen can be influenced by DNA sequence context, mutagen/carcinogen dose (and other changes in conditions), level of SOS induction, cell type and other factors. Thus, it is important to match the conditions of the adduct study versus the mutagen/carcinogen study as closely as possible. DNA sequence context can profoundly affect the quantitative and qualitative pattern of adduct mutagenesis, which is addressed. In vitro studies with DNA polymerases, frameshift mutagenesis and semi-targeted mutagenesis, whereby a mutation is induced near but not at the site of the adduct, are each discussed. Finally, the relationship between structural studies on adducts and mutagenesis is considered.

[1]  J. DiGiovanni,et al.  Targeted A --> T and G --> T mutations induced by site-specific deoxyadenosine and deoxyguanosine adducts, respectively, from the (+)-anti-diol epoxide of dibenz[a,j]anthracene in M13mp7L2. , 1996, Biochemistry.

[2]  N. Geacintov,et al.  The major, N2-Gua adduct of the (+)-anti-benzo[a]pyrene diol epoxide is capable of inducing G-->A and G-->C, in addition to G-->T, mutations. , 1995, Biochemistry.

[3]  E. Loechler How are potent bulky carcinogens able to induce such a diverse array of mutations? , 1995, Molecular carcinogenesis.

[4]  S. Hughes,et al.  Mutagenesis in Escherichia coli by three O6-substituted guanines in double-stranded or gapped plasmids. , 1995, Biochemistry.

[5]  L. S. Ripley,et al.  DNA nick processing by exonuclease and polymerase activities of bacteriophage T4 DNA polymerase accounts for acridine-induced mutation specificities in T4. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[6]  R. Lloyd,et al.  In vivo and in Vitro Replication Consequences of Stereoisomeric Benzo[a]pyrene-7,8-dihydrodiol 9,10-Epoxide Adducts on Adenine N6 at the Second Position of N-ras Codon 61 (*) , 1995, The Journal of Biological Chemistry.

[7]  E. Loechler,et al.  The major, N2-Gua adduct of the (+)-anti-benzo[a]pyrene diol epoxide can be unstable in double-stranded DNA. , 1995, Biochemistry.

[8]  P. Hanawalt Transcription-coupled repair and human disease. , 1994, Science.

[9]  N. Geacintov,et al.  Flanking base effects on the structural conformation of the (+)-trans-anti-benzo[a]pyrene diolepoxide adduct to N2-dG in sequence-defined oligonucleotides. , 1994, Carcinogenesis.

[10]  T. Krugh,et al.  Structural characterization of two interchangeable conformations of a 2-aminofluorene-modified DNA oligomer by NMR and energy minimization. , 1994, Biochemistry.

[11]  C. Harris,et al.  Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. , 1994, Cancer research.

[12]  D. Wink,et al.  DNA sequence changes induced by two nitric oxide donor drugs in the supF assay. , 1994, Chemical research in toxicology.

[13]  W. Thilly,et al.  N-nitroso-N-methylurea-induced rat mammary tumors arise from cells with preexisting oncogenic Hras1 gene mutations. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[14]  J. Jessee,et al.  Proximal and distal effects of sequence context on ultraviolet mutational hotspots in a shuttle vector replicated in xeroderma cells. , 1994, Journal of molecular biology.

[15]  I. Lambert,et al.  DNA sequence determinants of carcinogen-induced frameshift mutagenesis. , 1994, Biochemistry.

[16]  R. Lloyd,et al.  The replication fate of R- and S-styrene oxide adducts on adenine N6 is dependent on both the chirality of the lesion and the local sequence context. , 1993, The Journal of biological chemistry.

[17]  E. Loechler,et al.  AP sites are not significantly involved in mutagenesis by the (+)-anti diol epoxide of benzo[a]pyrene: the complexity of its mutagenic specificity is likely to arise from adduct conformational polymorphism. , 1993, Biochemistry.

[18]  E. Loechler,et al.  Mutational specificity of the (+)-anti-diol epoxide of benzo[a]pyrene in a supF gene of an Escherichia coli plasmid: DNA sequence context influences hotspots, mutagenic specificity and the extent of SOS enhancement of mutagenesis. , 1993, Carcinogenesis.

[19]  E. Loechler,et al.  Mutagenesis by the (+)-anti-diol epoxide of benzo[a]pyrene: what controls mutagenic specificity? , 1993, Biochemistry.

[20]  M. Moriya Single-stranded shuttle phagemid for mutagenesis studies in mammalian cells: 8-oxoguanine in DNA induces targeted G.C-->T.A transversions in simian kidney cells. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[21]  S. Lippard,et al.  Mutagenicity and genotoxicity of the major DNA adduct of the antitumor drug cis-diamminedichloroplatinum(II). , 1993, Biochemistry.

[22]  J. Groopman,et al.  Sequence specificity of aflatoxin B1-induced mutations in a plasmid replicated in xeroderma pigmentosum and DNA repair proficient human cells. , 1992, Cancer research.

[23]  M. Benasutti,et al.  Mutagenesis by (+)-anti-B[a]P-N2-Gua, the major adduct of activated benzo[a]pyrene, when studied in an Escherichia coli plasmid using site-directed methods. , 1992, Carcinogenesis.

[24]  J. Taylor,et al.  In vitro evidence that UV-induced frameshift and substitution mutations at T tracts are the result of misalignment-mediated replication past a specific thymine dimer. , 1992, Biochemistry.

[25]  I. Lambert,et al.  Carcinogen-induced frameshift mutagenesis in repetitive sequences. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[26]  D. Jerina,et al.  Dose-dependent differences in the profile of mutations induced by an ultimate carcinogen from benzo[a]pyrene. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[27]  J. Essigmann,et al.  3-Methyladenine mutagenesis under conditions of SOS induction in Escherichia coli. , 1991, Carcinogenesis.

[28]  J. Simon,et al.  A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[29]  J. Essigmann,et al.  Site-specific mutagenesis: retrospective and prospective. , 1991, Carcinogenesis.

[30]  J. Essigmann,et al.  Mechanistic studies of ionizing radiation and oxidative mutagenesis: genetic effects of a single 8-hydroxyguanine (7-hydro-8-oxoguanine) residue inserted at a unique site in a viral genome. , 1990, Biochemistry.

[31]  T. Reid,et al.  Mutagenesis by site-specific arylamine adducts in plasmid DNA: enhancing replication of the adducted strand alters mutation frequency. , 1990, Biochemistry.

[32]  E. Dogliotti,et al.  Site-specific mutagenesis by O6-alkylguanines located in the chromosomes of mammalian cells: influence of the mammalian O6-alkylguanine-DNA alkyltransferase. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[33]  R. Kumar,et al.  Molecular analysis of O6-substituted guanine-induced mutagenesis of ras oncogenes. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[34]  P. Koehl,et al.  Single adduct mutagenesis: strong effect of the position of a single acetylaminofluorene adduct within a mutation hot spot. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[35]  M. Z. Humayun,et al.  Mechanisms of mutagenesis by a bulky DNA lesion at the guanine N7 position. , 1988, Genetics.

[36]  J. E. Leclerc,et al.  Frequency and spectrum of mutations produced by a single cis-syn thymine-thymine cyclobutane dimer in a single-stranded vector. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[37]  M. Whitlow,et al.  Mapping the binding site of aflatoxin B1 in DNA: systematic analysis of the reactivity of aflatoxin B1 with guanines in different DNA sequences. , 1988, Biochemistry.

[38]  B. Strauss,et al.  Influence of template strandedness on in vitro replication of mutagen-damaged DNA. , 1987, Biochemistry.

[39]  J H Miller,et al.  Mutagenic specificity of ultraviolet light. , 1985, Journal of molecular biology.

[40]  M. Barbacid,et al.  Induction of mammary carcinomas in rats by nitroso-methylurea involves malignant activation of H-ras-1 locus by single point mutations , 1983, Nature.

[41]  D. Hanahan Studies on transformation of Escherichia coli with plasmids. , 1983, Journal of molecular biology.

[42]  E. Loechler,et al.  Are base substitution and frameshift mutagenesis pathways interrelated? An analysis based upon studies of the frequencies and specificities of mutations induced by the (+)-anti diol epoxide of benzo[a]pyrene. , 1995, Mutation research.

[43]  R. Jankowiak,et al.  Sequence dependence of benzo[a]pyrene diol epoxide-DNA adduct conformer distribution: a study by laser-induced fluorescence/polyacrylamide gel electrophoresis. , 1994, Chemical Research in Toxicology.

[44]  John Davis Groopman,et al.  The toxicology of aflatoxins: human health, veterinary and agricultural significance. , 1993 .

[45]  D. Reardon,et al.  DNA polymerase action on bulky deoxyguanosine and deoxyadenosine adducts. , 1990, Carcinogenesis.

[46]  E. Seeberg,et al.  Acetylaminofluorene bound to different guanines of the sequence -GGCGCC- is excised with different efficiencies by the UvrABC excision nuclease in a pattern not correlated to the potency of mutation induction. , 1990, Proceedings of the National Academy of Sciences of the United States of America.