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. 1994 Mar;136(3):731–746. doi: 10.1093/genetics/136.3.731

Complex Frameshift Mutations Mediated by Plasmid Pkm101: Mutational Mechanisms Deduced from 4-Aminobiphenyl-Induced Mutation Spectra in Salmonella

J G Levine 1, R M Schaaper 1, D M DeMarini 1
PMCID: PMC1205880  PMID: 8005429

Abstract

We used colony probe hybridization and polymerase chain reaction/DNA sequence analysis to determine the mutations in ~2,400 4-aminobiphenyl (4-AB) +S9-induced revertants of the -1 frameshift allele hisD3052 and of the base-substitution allele hisG46 of Salmonella typhimurium. Most of the mutations occurred at sites containing guanine, which is the primary base at which 4-AB forms DNA adducts. A hotspot mutation involving the deletion of a CG or GC within the sequence CGCGCGCG accounted for 100 and 99.9%, respectively, of the reversion events at the hisD3052 allele in the pKM101 plasmid-minus strains TA1978 (uvr(+)) and TA1538 (δuvrB). In strain TA98 (δuvrB, pKM101), which contained the SOS DNA repair system provided by the pKM101 plasmid, ~85% of the revertants also contained the hotspot deletion; the remaining ~15% contained one of two types of mutations: (1) complex frameshifts that can be described as a -2 or + 1 frameshift and an associated base substitution and (2) deletions of the CC or GG sequences that flank the hotspot site (CCGCGCGCGG). We propose a misincorporation/slippage model to account for these mutations in which (1) pKM101-mediated misincorporation and translesion synthesis occurs across a 4-AB-adducted guanine; (2) the instability of such a mispairing and/or the presence of the adduct leads to strand slippage in a run of repeated bases adjacent to the adducted guanine; and (3) continued DNA synthesis from the slipped intermediate produces a frameshift associated with a base substitution. This model readily accounts for the deletion of the CC or GG sequences flanking the hotspot site, indicating that these mutations are, in fact, complex mutations in disguise (i.e., cryptic complex frameshifts). The inferred base-substitution specificity associated with the complex frameshifts at the hisD3052 allele (primarily G·C -> T·A transversions) is consistent with the finding that 4-AB induced primarily G·C -> T·A transversions at the hisG46 base-substitution allele. The model also provides a framework for understanding the different relative mutagenic potencies of 4-AB at the two alleles in the various DNA repair backgrounds of Salmonella.

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Selected References

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  1. Adams W. T., Skopek T. R. Statistical test for the comparison of samples from mutational spectra. J Mol Biol. 1987 Apr 5;194(3):391–396. doi: 10.1016/0022-2836(87)90669-3. [DOI] [PubMed] [Google Scholar]
  2. Bebenek K., Roberts J. D., Kunkel T. A. The effects of dNTP pool imbalances on frameshift fidelity during DNA replication. J Biol Chem. 1992 Feb 25;267(6):3589–3596. [PubMed] [Google Scholar]
  3. Beland F. A., Beranek D. T., Dooley K. L., Heflich R. H., Kadlubar F. F. Arylamine-DNA adducts in vitro and in vivo: their role in bacterial mutagenesis and urinary bladder carcinogenesis. Environ Health Perspect. 1983 Mar;49:125–134. doi: 10.1289/ehp.8349125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bennett C. B., Luo X., Refolo L. M., Humayun M. Z. Effects of SOS and MucAB functions on reactivation and mutagenesis of M13 replicative form DNA bearing bulky lesions. Mutat Res. 1988 Nov;202(1):223–234. doi: 10.1016/0027-5107(88)90186-8. [DOI] [PubMed] [Google Scholar]
  5. Blanco M., Herrera G., Aleixandre V. Different efficiency of UmuDC and MucAB proteins in UV light induced mutagenesis in Escherichia coli. Mol Gen Genet. 1986 Nov;205(2):234–239. doi: 10.1007/BF00430433. [DOI] [PubMed] [Google Scholar]
  6. Bookland E. A., Reznikoff C. A., Lindstrom M., Swaminathan S. Induction of thioguanine-resistant mutations in human uroepithelial cells by 4-aminobiphenyl and its N-hydroxy derivatives. Cancer Res. 1992 Mar 15;52(6):1615–1621. [PubMed] [Google Scholar]
  7. Broyde S., Hingerty B. E., Srinivasan A. R. Influence of the carcinogen 4-aminobiphenyl on DNA conformation. Carcinogenesis. 1985 May;6(5):719–725. doi: 10.1093/carcin/6.5.719. [DOI] [PubMed] [Google Scholar]
  8. Burnouf D., Koehl P., Fuchs R. P. Single adduct mutagenesis: strong effect of the position of a single acetylaminofluorene adduct within a mutation hot spot. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4147–4151. doi: 10.1073/pnas.86.11.4147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cho B. P., Beland F. A., Marques M. M. NMR structural studies of a 15-mer DNA sequence from a ras protooncogene, modified at the first base of codon 61 with the carcinogen 4-aminobiphenyl. Biochemistry. 1992 Oct 13;31(40):9587–9602. doi: 10.1021/bi00155a011. [DOI] [PubMed] [Google Scholar]
  10. Cliet I., Fournier E., Melcion C., Cordier A. In vivo micronucleus test using mouse hepatocytes. Mutat Res. 1989 Dec;216(6):321–326. doi: 10.1016/0165-1161(89)90042-3. [DOI] [PubMed] [Google Scholar]
  11. DeMarini D. M., Bell D. A., Levine J. G., Shelton M. L., Abu-Shakra A. Molecular analysis of mutations induced at the hisD3052 allele of Salmonella by single chemicals and complex mixtures. Environ Health Perspect. 1993 Oct;101 (Suppl 3):207–212. doi: 10.1289/ehp.93101s3207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Drake J. W., Baltz R. H. The biochemistry of mutagenesis. Annu Rev Biochem. 1976;45:11–37. doi: 10.1146/annurev.bi.45.070176.000303. [DOI] [PubMed] [Google Scholar]
  13. Eisenstadt E., Miller J. K., Kahng L. S., Barnes W. M. Influence of uvrB and pKM101 on the spectrum of spontaneous, UV- and gamma-ray-induced base substitutions that revert hisG46 in Salmonella typhimurium. Mutat Res. 1989 Jan;210(1):113–125. doi: 10.1016/0027-5107(89)90050-x. [DOI] [PubMed] [Google Scholar]
  14. Fishel R. A., Detmer K., Rich A. Identification of homologous pairing and strand-exchange activity from a human tumor cell line based on Z-DNA affinity chromatography. Proc Natl Acad Sci U S A. 1988 Jan;85(1):36–40. doi: 10.1073/pnas.85.1.36. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fowler R. G., McGinty L., Mortelmans K. E. Spontaneous mutational specificity of drug resistance plasmid pKM101 in Escherichia coli. J Bacteriol. 1979 Dec;140(3):929–937. doi: 10.1128/jb.140.3.929-937.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fuscoe J. C., Wu R., Shen N. H., Healy S. K., Felton J. S. Base-change analysis of revertants of the hisD3052 allele in Salmonella typhimurium. Mutat Res. 1988 Sep;201(1):241–251. doi: 10.1016/0027-5107(88)90131-5. [DOI] [PubMed] [Google Scholar]
  17. Garcia A., Lambert I. B., Fuchs R. P. DNA adduct-induced stabilization of slipped frameshift intermediates within repetitive sequences: implications for mutagenesis. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5989–5993. doi: 10.1073/pnas.90.13.5989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hartman P. E., Ames B. N., Roth J. R., Barnes W. M., Levin D. E. Target sequences for mutagenesis in Salmonella histidine-requiring mutants. Environ Mutagen. 1986;8(4):631–641. doi: 10.1002/em.2860080414. [DOI] [PubMed] [Google Scholar]
  19. Inman M. A., Butler M. A., Connor T. H., Matney T. S. The effects of excision repair and the plasmid pKM101 on the induction of his+ revertants by chemical agents in Salmonella typhimurium. Teratog Carcinog Mutagen. 1983;3(6):491–501. doi: 10.1002/1520-6866(1990)3:6<491::aid-tcm1770030605>3.0.co;2-3. [DOI] [PubMed] [Google Scholar]
  20. Ioannides C., Lewis D. F., Trinick J., Neville S., Sertkaya N. N., Kajbaf M., Gorrod J. W. A rationale for the non-mutagenicity of 2- and 3-aminobiphenyls. Carcinogenesis. 1989 Aug;10(8):1403–1407. doi: 10.1093/carcin/10.8.1403. [DOI] [PubMed] [Google Scholar]
  21. Isono K., Yourno J. Chemical carcinogens as frameshift mutagens: Salmonella DNA sequence sensitive to mutagenesis by polycyclic carcinogens. Proc Natl Acad Sci U S A. 1974 May;71(5):1612–1617. doi: 10.1073/pnas.71.5.1612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kadlubar F. F., Dooley K. L., Teitel C. H., Roberts D. W., Benson R. W., Butler M. A., Bailey J. R., Young J. F., Skipper P. W., Tannenbaum S. R. Frequency of urination and its effects on metabolism, pharmacokinetics, blood hemoglobin adduct formation, and liver and urinary bladder DNA adduct levels in beagle dogs given the carcinogen 4-aminobiphenyl. Cancer Res. 1991 Aug 15;51(16):4371–4377. [PubMed] [Google Scholar]
  23. Kunkel T. A. Misalignment-mediated DNA synthesis errors. Biochemistry. 1990 Sep 4;29(35):8003–8011. doi: 10.1021/bi00487a001. [DOI] [PubMed] [Google Scholar]
  24. Kunkel T. A., Soni A. Mutagenesis by transient misalignment. J Biol Chem. 1988 Oct 15;263(29):14784–14789. [PubMed] [Google Scholar]
  25. Kupchella E., Cebula T. A. Analysis of Salmonella typhimurium hisD3052 revertants: the use of oligodeoxyribonucleotide colony hybridization, PCR, and direct sequencing in mutational analysis. Environ Mol Mutagen. 1991;18(4):224–230. doi: 10.1002/em.2850180404. [DOI] [PubMed] [Google Scholar]
  26. Lambert I. B., Gordon A. J., Glickman B. W., McCalla D. R. The influence of local DNA sequence and DNA repair background on the mutational specificity of 1-nitroso-8-nitropyrene in Escherichia coli: inferences for mutagenic mechanisms. Genetics. 1992 Dec;132(4):911–927. doi: 10.1093/genetics/132.4.911. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lambert I. B., Napolitano R. L., Fuchs R. P. Carcinogen-induced frameshift mutagenesis in repetitive sequences. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1310–1314. doi: 10.1073/pnas.89.4.1310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lasko D. D., Harvey S. C., Malaikal S. B., Kadlubar F. F., Essigmann J. M. Specificity of mutagenesis by 4-aminobiphenyl. A possible role for N-(deoxyadenosin-8-yl)-4-aminobiphenyl as a premutational lesion. J Biol Chem. 1988 Oct 25;263(30):15429–15435. [PubMed] [Google Scholar]
  29. Marques M. M., Beland F. A. Synthesis, characterization, and solution properties of ras sequences modified by arylamine carcinogens at the first base of codon 61. Chem Res Toxicol. 1990 Nov-Dec;3(6):559–565. doi: 10.1021/tx00018a011. [DOI] [PubMed] [Google Scholar]
  30. Mattern I. E., Olthoff-Smit F. P., Jacobs-Meijsing B. L., Enger-Valk B. E., Pouwels P. H., Lohman P. H. A system to determine basepair substitutions at the molecular level, based on restriction enzyme analysis; influence of the muc genes of pKM101 on the specificity of mutation induction in E. coli. Mutat Res. 1985 Jan-Feb;148(1-2):35–45. doi: 10.1016/0027-5107(85)90205-2. [DOI] [PubMed] [Google Scholar]
  31. Nohmi T., Hakura A., Nakai Y., Watanabe M., Murayama S. Y., Sofuni T. Salmonella typhimurium has two homologous but different umuDC operons: cloning of a new umuDC-like operon (samAB) present in a 60-megadalton cryptic plasmid of S. typhimurium. J Bacteriol. 1991 Feb;173(3):1051–1063. doi: 10.1128/jb.173.3.1051-1063.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. O'Hara S. M., Marnett L. J. DNA sequence analysis of spontaneous and beta-methoxy-acrolein-induced mutations in Salmonella typhimurium hisD3052. Mutat Res. 1991 Mar;247(1):45–56. doi: 10.1016/0027-5107(91)90032-j. [DOI] [PubMed] [Google Scholar]
  33. Oeschger N. S., Hartman P. E. ICR-induced frameshift mutations in the histidine operon of Salmonella. J Bacteriol. 1970 Feb;101(2):490–504. doi: 10.1128/jb.101.2.490-504.1970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Oller A. R., Rastogi P., Morgenthaler S., Thilly W. G. A statistical model to estimate variance in long term-low dose mutation assays: testing of the model in a human lymphoblastoid mutation assay. Mutat Res. 1989 Jun;216(3):149–161. doi: 10.1016/0165-1161(89)90001-0. [DOI] [PubMed] [Google Scholar]
  35. Prival M. J., Cebula T. A. Sequence analysis of mutations arising during prolonged starvation of Salmonella typhimurium. Genetics. 1992 Oct;132(2):303–310. doi: 10.1093/genetics/132.2.303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Refolo L. M., Bennett C. B., Humayun M. Z. Mechanisms of frameshift mutagenesis by aflatoxin B1-2,3-dichloride. J Mol Biol. 1987 Feb 20;193(4):609–636. doi: 10.1016/0022-2836(87)90344-5. [DOI] [PubMed] [Google Scholar]
  37. Ripley L. S. Frameshift mutation: determinants of specificity. Annu Rev Genet. 1990;24:189–213. doi: 10.1146/annurev.ge.24.120190.001201. [DOI] [PubMed] [Google Scholar]
  38. Sambamurti K., Callahan J., Luo X., Perkins C. P., Jacobsen J. S., Humayun M. Z. Mechanisms of mutagenesis by a bulky DNA lesion at the guanine N7 position. Genetics. 1988 Dec;120(4):863–873. doi: 10.1093/genetics/120.4.863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Schaaper R. M., Koffel-Schwartz N., Fuchs R. P. N-acetoxy-N-acetyl-2-aminofluorene-induced mutagenesis in the lacI gene of Escherichia coli. Carcinogenesis. 1990 Jul;11(7):1087–1095. doi: 10.1093/carcin/11.7.1087. [DOI] [PubMed] [Google Scholar]
  40. Shapiro R., Underwood G. R., Zawadzka H., Broyde S., Hingerty B. E. Conformation of d(CpG) modified by the carcinogen 4-aminobiphenyl: a combined experimental and theoretical analysis. Biochemistry. 1986 Apr 22;25(8):2198–2205. doi: 10.1021/bi00356a052. [DOI] [PubMed] [Google Scholar]
  41. Shelby M. D., Gulati D. K., Tice R. R., Wojciechowski J. P. Results of tests for micronuclei and chromosomal aberrations in mouse bone marrow cells with the human carcinogens 4-aminobiphenyl, treosulphan, and melphalan. Environ Mol Mutagen. 1989;13(4):339–342. doi: 10.1002/em.2850130410. [DOI] [PubMed] [Google Scholar]
  42. Smith C. M., Eisenstadt E. Identification of a umuDC locus in Salmonella typhimurium LT2. J Bacteriol. 1989 Jul;171(7):3860–3865. doi: 10.1128/jb.171.7.3860-3865.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Steele C. M., Ioannides C. Induction of rat hepatic mixed function oxidases by aromatic amines and its relationship to their bioactivation to mutagens. Mutat Res. 1986 Aug;162(1):41–46. doi: 10.1016/0027-5107(86)90069-2. [DOI] [PubMed] [Google Scholar]
  44. Streisinger G., Okada Y., Emrich J., Newton J., Tsugita A., Terzaghi E., Inouye M. Frameshift mutations and the genetic code. This paper is dedicated to Professor Theodosius Dobzhansky on the occasion of his 66th birthday. Cold Spring Harb Symp Quant Biol. 1966;31:77–84. doi: 10.1101/sqb.1966.031.01.014. [DOI] [PubMed] [Google Scholar]
  45. Streisinger G., Owen J. Mechanisms of spontaneous and induced frameshift mutation in bacteriophage T4. Genetics. 1985 Apr;109(4):633–659. doi: 10.1093/genetics/109.4.633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Suzuki M., Takahashi K., Morita T., Kojima M., Tada M. The action of 4-hydroxyaminobiphenyl in Escherichia coli: cytotoxic and mutagenic effects in DNA repair deficient strains. Mutat Res. 1993 Feb;301(2):125–134. doi: 10.1016/0165-7992(93)90035-t. [DOI] [PubMed] [Google Scholar]
  47. Tamura N., King C. M. Comparative survival of aminobiphenyl- and aminofluorene-substituted plasmid DNA in Escherichia coli Uvr endonuclease deficient strains. Carcinogenesis. 1990 Apr;11(4):535–540. doi: 10.1093/carcin/11.4.535. [DOI] [PubMed] [Google Scholar]
  48. Topal M. D., Fresco J. R. Complementary base pairing and the origin of substitution mutations. Nature. 1976 Sep 23;263(5575):285–289. doi: 10.1038/263285a0. [DOI] [PubMed] [Google Scholar]
  49. Tripathy N. K., Würgler F. E., Frei H. Genetic toxicity of six carcinogens and six non-carcinogens in the Drosophila wing spot test. Mutat Res. 1990 Nov;242(3):169–180. doi: 10.1016/0165-1218(90)90082-d. [DOI] [PubMed] [Google Scholar]
  50. Veaute X., Fuchs R. P. Greater susceptibility to mutations in lagging strand of DNA replication in Escherichia coli than in leading strand. Science. 1993 Jul 30;261(5121):598–600. doi: 10.1126/science.8342022. [DOI] [PubMed] [Google Scholar]
  51. Walker G. C. Mutagenesis and inducible responses to deoxyribonucleic acid damage in Escherichia coli. Microbiol Rev. 1984 Mar;48(1):60–93. doi: 10.1128/mr.48.1.60-93.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Woodgate R., Levine A. S., Koch W. H., Cebula T. A., Eisenstadt E. Induction and cleavage of Salmonella typhimurium UmuD protein. Mol Gen Genet. 1991 Sep;229(1):81–85. doi: 10.1007/BF00264216. [DOI] [PubMed] [Google Scholar]

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