Skip to main content
SpringerLink
Log in

Stress response induced by DNA damage leads to specific, delayed and untargeted mutations

  • Published:
Molecular and General Genetics MGG Aims and scope Submit manuscript

Summary

Cells of the mouse T-lymphoma line GRSL13 were treated with 8-methoxy-psoralen plus longwave ultraviolet light (PUVA) under conditions where the biological effects are mainly due to non-persistent DNA crosslinks (PUVA-CL treatment). Fluctuation analysis showed that PUVA-CL treatment resulted in an enhancement of the mutation rate in the progeny of treated cells, which persisted until the eleventh generation after treatment. Since only 5 cross-links are available to account for 52 mutational events observed in the coding region, about 90% of the induced mutational events must have been untargeted. This was confirmed by molecular analysis of these mutations, which showed that 53% of the point mutations arose at sites which are not a target for psoralens. This supports the hypothesis that stress responses may give rise to untargeted mutagenesis. Further support for this hypothesis is provided by the observation that 8-methoxy-psoralen (8-MOP) or UVA alone (both of which are known to induce many pleiotropic effects) each acted as indirect mutagen by enhancing the mutation rate 2–4 fold in the progeny of treated cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abrahams PJ, Huitema BA, Van der Eb AJ (1984) Enhanced reactivation and enhanced mutagenesis of Herpes Simplex Virus in normal human and xeroderma pigmentosum cells. Mol Cell Biol 4:2341–2346

    Google Scholar 

  • Averbeck D (1989) Recent advances in psoralen phototoxicity mechanism. J Photochem Photobiol 50:859–882

    Google Scholar 

  • Averbeck D, Dardalhon M, Magana-Schwencke N (1990) Repair of furocoumarin-plus-UVA-induced demage and mutagenic consequences in eukaryotic cells. J Photochem Photobiol B 6:221–236

    Google Scholar 

  • Barrett JC, Elmore E (1985) Comparison of Carcinogenesis and mutagenesis of mammalian cells in culture. In: Likhachev R, Anisimov V, Montesano R (eds) Age-related factors in Carcinogenesis, IARC Scientific Publ, Lyon pp 171–206

    Google Scholar 

  • Boesen JJB, Lohman PHM, Simons JWIM (1991) Concomitant induction of signal transduction pathways and genetic instability by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate. Carcinogenesis 3:487–492

    Google Scholar 

  • Bridges BA, Mottershead RP (1977) Frameshift mutagenesis in bacteria by 8-methoxypsoralen (methoxalen) in the dark. Mutation Res 44:305–312

    Google Scholar 

  • Bull P, Hunter T, Verma IM (1989) Transcriptional induction of the murine c-rel gene with serum and phorbol-12-myristate-13-acetate in fibroblasts. Mol Cell Biol 9:5239–5243

    Google Scholar 

  • Burger PM, Simons JWIM (1979a) Mutagenicity of 8-methoxypsoralen and long-wave ultraviolet irradiation in V-79 Chinese hamster cells. Mutation Res 60:381–389

    Google Scholar 

  • Burger PM, Simons JWIM (1979b) Mutagenicity of 8-methoxypsoralen and long wave ultraviolet irradiation in diploid human skin fibroblasts. Mutation Res 63:371–380

    Google Scholar 

  • Burki HJ, Lam C-K, Wood RD (1980) UV-light-induced mutations in synchronous CHO cells. Mutation Res 69:347–356

    Google Scholar 

  • Cadet J, Voituriez L, Nardin R, Viari A, Vigny P (1988) A new class of psoralen photoadducts to DNA components: isolation and characterization of 8-MOP adducts to the osidic moiety of 2′-deoxyadenosine. J Photochem Photobiol B 2:321–339

    Google Scholar 

  • Caillet-Fauquet P, Maenhaut-Michel G, Radman M (1984) SOS mutator effect in E. coli mutants deficient in mismatch correction. EMBO J 3:707–712

    Google Scholar 

  • Caillet-Fauquet P, Maenhaut-Michel G (1988) Nature of the SOS mutator activity: genetic characterization of untargeted mutagenesis in Escherichia coli. Mol Gen Genet 213:491–498

    Google Scholar 

  • Capizzi RL, Jameson JW (1973) A table for the estimation of the spontaneous mutation rate of cells in culture. Mutation Res 17:147–148

    Google Scholar 

  • Colamonici OR, Trepel JB, Vidal CA, Neckers LM (1986) Phorbol ester induces c-sis gene transcription in stem cell line K-562. Mol Cell Biol 6:1847–1850

    Google Scholar 

  • Dardalhon M, Averbeck D (1988) Induction and removal of DNA interstrand cross-links in V79 Chinese hamster cells measured by hydroxylapatite chromatography after treatments with bifunctional furocoumarins. Int J Radiat Biol 54:1007–1020

    Google Scholar 

  • Das Gupta UM, Summers WC (1978) Ultraviolet reactivation of herpes simplex virus is mutagenic and inducible in mammalian cells. Proc Natl Acad Sci USA 75:2378–2381

    Google Scholar 

  • Dullens HFJ, Hilgers J, Van Basten CDH, De Weger RA, De Heer E, Den Otter W (1982) Cell surface antigen phenotypes and enzyme expression patterns of two murine T-cell lymphomas derived from early and/or mature thymus cells. Leukemia Res 6:425–428

    Google Scholar 

  • Elespuru RK (1987) Inducible responses to DNA damage in bacteria and mammalian cells. Env Mol Mutagenesis 10:97–116

    Google Scholar 

  • Enninga I, Groenendijk RTL, Van Zeeland AA, Simons JWIM (1985) Differential response of human fibroblasts to the cytotoxic and mutagenic effects of UV radiation in different phases of the cell cycle. Mutation Res 148:119–128

    Google Scholar 

  • Enninga I, Groenendijk RTL, Filon AR, Van Zeeland AA, Simons JWIM (1986) The wavelength dependence of UV-induced pyrimidine dimer formation, cell killing and mutation induction in human diploid skin fibroblasts. Carcinogenesis 7:1829–1836

    Google Scholar 

  • Fornace AJ, Alamo I, Hollander MC (1988) DNA damage-inducible transcripts in mammalian cells. Proc Natl Acad Sci USA 85:8800–8804

    Google Scholar 

  • Fornace AJ, Zmudzka B, Hollander MC, Wilson SH (1989) Induction of β-polymerase mRNA by DNA-damaging agents in Chinese hamster ovary cells. Mol Cell Biol 9:851–853

    Google Scholar 

  • Fujiwara Y, Tatsumi M (1977) Cross-link repair in human cells and its possible defect in Fanconi's anemia cells. J Mol Biol 113:635–649

    Google Scholar 

  • Glantz, SA (1989) Alternatives of analysis of variance and the t-test based on ranks. In: Kaufman-Barry B, White J (eds) Primer of biostatistics, McGraw-Hill, Singapore, pp 302–310

    Google Scholar 

  • Górski G, Antosz H, Gawron A (1991) Effect of 8-methoxypsoralen in the dark on proliferation of stimulated lymphocytes. J Pharm Pharmacol 43:63–64

    Google Scholar 

  • Greenberg ME, Ziff EB (1984) Stimulation of 3T3 cells induces transcription of the c-fos protooncogene. Nature 311:433–438

    Google Scholar 

  • Hearst JE, Isaacs ST, Kanne D, Rapoport H, Straub K (1984) The reaction of the psoralens with deoxyribonucleic acid. Quart Rev Biophys 17:1–44

    Google Scholar 

  • Herrlich P (1988) Endogenous cellular contributions to mammalian mutagenesis. In: Moses R, Summers WC (eds) DNA replication and mutagenesis, American Society for Microbiology, Washington DC, pp 457–464

    Google Scholar 

  • Hollander MC, Fornace AJ (1989) Induction of fos RNA by DNA-damaging agents. Cancer Res 49:1687–1692

    Google Scholar 

  • Islas AL, Vos JMH, Hanawalt PC (1991) Differential introduction and repair of psoralen photoadducts to DNA in specific human genes. Cancer Res 51:2867–2873

    Google Scholar 

  • Kirkland DJ, Creed KL, Mannisto P (1983) Comparative bacterial mutagenicity studies with 8-methoxypsoralen 4,5′,8-trimethyl-psoralen in the presence of near-ultraviolet light and in the dark. Mutation Res 116:73–82

    Google Scholar 

  • Knaap AGAC, Simons JWIM (1983) Ascertainment of the effect of differential growth rates of mutants on observed mutant frequencies in X-irradiated mammalian cells. An indication for the occurrence of X-ray-induced untargeted mutagenesis. Mutation Res 110:413–422

    Google Scholar 

  • Kohn KW, Ewig RAG, Erickson LC, Zwelling LA (1981) Measurement of strand breaks and cross-links by alkaline elution. In: Friedberg EC, Hanawalt PC (ed) DNA repair: A laboratory manual of research procedures, Vol 1, Part B, Marcel Dekker, New York, pp 379–401

    Google Scholar 

  • Kunz BA, Glickman BW (1984) The role of pyrimidine dimers as premutagenic lesions: a study of targeted vs untargeted mutagenesis in the lac I gene of Escherichia coli. Genetics 106:347–364

    Google Scholar 

  • Lambert ME, Ronai ZA, Weinstein IB, Carrels JI (1989) Enhancement of Major Histocompatibility Class I protein synthesis by DNA damage in cultured human fibroblasts and keratinocytes. Mol Cell Biol 9:847–850

    Google Scholar 

  • Lamph WW, Wamsley P, Sassone-Corsi P, Verma IM (1988) Induction of photo-oncogene JUN/AP-1 by serum and TPA. Nature 334:629–631

    Google Scholar 

  • Laskin JD, Lee E, Yurkow EJ, Laskin DL, Gallo MA (1985) A possible mechanism of psoralen phototoxicity not involving direct interaction with DNA. Proc Natl Acad Sci USA 82:6158–6162

    Google Scholar 

  • Lawrence CW, Christensen RE (1982) The mechanism of untargeted mutagenesis in UV-irradiated yeast. Mol Gen Genet 186:1–9

    Google Scholar 

  • Lindelöf B, Sigurgeirsson B, Tegner E, Larkö O, Johannesson A, Berne B, Christensen OB, Andersson T, Törngren M, Molin L, Nylander-Lundqvist E, Emtestam L (1991) PUVA and cancer: a large-scale epidemiological study. Lancet 338:91–93

    Google Scholar 

  • Little JB, Gorgojo L, Vetroos H (1990) Delayed appearance of lethal and specific gene mutations in irradiated mammalian cells. Int J Radiation Oncology Biol Phys 19:1425–1429

    Google Scholar 

  • Livneh Z (1983) Directed mutagenesis method for analysis of mutagen specificity: application to ultraviolet-induced mutagenesis. Proc Natl Acad Sci USA 80:237–241

    Google Scholar 

  • Luria SE, Delbrück M (1943) Mutations of bacteria from virus-sensitivity to virus-resistance. Genetics 28:491–511

    Google Scholar 

  • Miller JH, Brooks Low K (1984) Specificity of mutagenesis resulting from the induction of the SOS system in the absence of mutagenic treatment. Cell 37:675–682

    Google Scholar 

  • Miskin R, Reich E (1980) Plasminogen activator: induction of synthesis by DNA damage. Cell 19:217–224

    Google Scholar 

  • Moustacchi E (1991) Repair control of photo-induced cross-links and monoadducts in DNA: genetic, molecular and evolutionary features. In: Riklis E (ed) Photobiology, Plenum Press, New York, pp 223–233

    Google Scholar 

  • Nishizuka Y (1986) Studies and perspectives of protein kinase C. Science 233:305–312

    Google Scholar 

  • Nocentini S (1986) DNA photobinding of 7-methylpyrido-[3,4-c]-psoralen and 8-methoxypsoralen. Mutation Res 161:181–192

    Google Scholar 

  • Papadopoulo D, Averbeck D, Moustacchi E (1986) Mutagenic effects photo-induced in mammalian cells in vitro by two monofunctional pyridopsoralen. Photochem Photobiol 44:31–39

    Google Scholar 

  • Plooy ACM, Van Dijk M, Lohman PHM (1984) Induction and repair of DNA cross-links in Chinese hamster ovary cells treated with various platinum coordination compounds in relation to platinum binding to DNA, cytotoxicity, mutagenicity and antitumour activity. Cancer Res 44:2043–2051

    Google Scholar 

  • Quinto I, Averbeck D, Moustacchi E, Hrisoho Z, Moron J (1984) Frameshift mutagenicity in Salmonella typhimurium of furocoumarins in the dark. Mutation Res 136:49–54

    Google Scholar 

  • Riddle JC, Hsie AW (1978) An effect of cell cycle position on ultraviolet light-induced mutagenesis in Chinese hamster ovary cells. Mutation Res 52:409–420

    Google Scholar 

  • Roilides E, Munson PJ, Levine AS, Dixon K (1988) Use of a Simian Virus 40-based shuttle vector to analyze enhanced mutagenesis in mitomycin C-treated monkey cells. Moll Cell Biol 8:3943–3946

    Google Scholar 

  • Ronai ZA, Okin E, Weinstein IB (1988) Ultraviolet light induces the expression of oncogenes in rat fibroblast and human keratinocyte cells. Oncogene 2:201–204

    Google Scholar 

  • Sage E, Moustacchi E (1987) Sequence context effects on 8-methoxypsoralen photobinding to defined DNA fragments. Biochemistry 26:3307–3314

    Google Scholar 

  • Sarasin A (1985) SOS response in mammalian cells. Cancer Inv 3:163–174

    Google Scholar 

  • Sassanfar M, Roberts JW (1990) Nature of the SOS-inducing signal in E. coli. J Mol Biol 212:79–96

    Google Scholar 

  • Sinden RR, Hagerman PJ (1984) Interstrand psoralen cross-links do not introduce appreciable bends in DNA. Biochemistry 23:6299–6303

    Google Scholar 

  • Southern EM (1975) Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol 98:503–517

    Google Scholar 

  • Stern RS, Laird N, Melski J, Parrish JA, Fitzpatrick TB, Bleich HL (1984) Cutaneous squamous cell carcinoma in patients treated with PUVA. New Engl J Med 30:1156–1161

    Google Scholar 

  • Sullivan NF, Willis AE (1989) Elevation of c-myc by DNA strand breakage. Oncogene 4:1497–1502

    Google Scholar 

  • Swart RNJ, Beckers MAN, Schothorst AA (1983) Phototoxicity and mutagenicity of 4,5′-dimethyl angelicin and long-wave ultraviolet irradiation in Chinese hamster cells and human skin fibroblasts. Mutation Res 124:271–279

    Google Scholar 

  • Tessman JW, Isaacs ST, Hearst JE (1985) Photochemistry of the furan-side 8-methoxypsoralen-thymidine monoadduct inside the DNA helix. Conversion to diadduct and to pyrone-side monoadduct. Biochemistry 24:1669–1676

    Google Scholar 

  • Varshavsky A (1981) Phorbol ester dramatically increases incidence of methotrexate-resistant mouse cells; Possible mechanism and relevance to tumor promotion. Cell 25:561–572

    Google Scholar 

  • Vindelov LL, Christensen IJ, Nissen NI (1983) A detergent-trypsin method for the preparation of nuclei for flow cytometric DNA analysis. Cytometry 3:323–327

    Google Scholar 

  • Vos JMH, Hanawalt PC (1987) Processing of psoralen adducts in an active human gene: Repair and replication of DNA containing monoadducts and interstrand cross-links. Cell 50:789–799

    Google Scholar 

  • Vrieling H, Simons JWIM, Zeeland AA (1988) Nucleotide sequence determination of point mutations at the mouse hprt locus using in vitro amplification of hprt mRNA sequences. Mutation Res 198:107–113

    Google Scholar 

  • Witkin EM, Wermundsen IE (1979) Targeted and untargeted mutagenesis by various inducers of SOS functions in Escherichia coli. Cold Spring Harbor Symp Quant Biol 43:881–886

    Google Scholar 

  • Yatagai F, Horsfall MJ, Glickmann BW (1987) Defect in excision repair alters the mutational specificity of PUVA treatment in the lacI gene of E. coli. J Mol Biol 194:601–607

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. MGC-Department of Radiation Genetics and Chemical Mutagenesis, University of Leiden, Wassenaarseweg 72, NL-2333, AL Leiden, The Netherlands

    Jan J. B. Boesen, Sandrine Stuivenberg, Corné H. M. Thyssens, Henk Panneman, Firouz Darroudi, Paul H. M. Lohman & Jo W. I. M. Simons

Authors
  1. Jan J. B. Boesen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandrine Stuivenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Corné H. M. Thyssens
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Henk Panneman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Firouz Darroudi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paul H. M. Lohman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jo W. I. M. Simons
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Communicated by R. Devoret

Rights and permissions

Reprints and permissions

About this article

Cite this article

Boesen, J.J.B., Stuivenberg, S., Thyssens, C.H.M. et al. Stress response induced by DNA damage leads to specific, delayed and untargeted mutations. Molec. Gen. Genet. 234, 217–227 (1992). https://doi.org/10.1007/BF00283842

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00283842

Key words

Search

Navigation