Molecular Crosstalks at Carcinogen-DNA Adducts

  • Hanspeter Naegeli
Part of the Molecular Biology Intelligence Unit book series (MBIU)


To avoid damage-induced mutagenesis and minimize cytotoxicity, carcinogen-DNA adducts should be immediately channeled into appropriate repair pathways. Problems may arise, however, when a damaged sequence serves as a substrate not only for DNA repair but, simultaneously, for other nuclear functions such as transcription, replication or homologous recombination. These different processes may interfere with each other by competing for the same DNA substrate. For example, it is well established that many base lesions constitute effective blocks to transcription1 and replication.2 Analysis of UV-induced mutations in SUP4-o (a yeast transfer RNA gene transcribed by RNA polymerase III) demonstrated a strong strand bias with approximately 90% of the nucleotide sequence changes in the transcribed template strand.3 This observation indicates that excision repair in transfer RNA genes is inhibited by concurrent transcription. Exactly the opposite is observed in genes transcribed by eukaryotic RNA polymerase II, where excision repair of the transcribed template strand is stimulated by transcription.4 Thus, RNA (and DNA) polymerases are important modulators of the biological consequences of DNA damage. The role of transcription and replication in the cellular response to genotoxic insults will be reviewed in chapters 9 and 10.


Excision Repair High Mobility Group Molecular Crosstalk Intrastrand Crosslinks Platinum Adduct 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Michalke H, Bremer H. RNA synthesis in Escherichia coli after irradiation with ultraviolet light. J Mol Biol 1969; 41:1–23.CrossRefGoogle Scholar
  2. 2.
    Moore PD, Bose KK, Rabkin SD et al. Sites of termination of in vitro DNA synthesis on ultraviolet-and N-acetylaminofluorene-treated φX174 templates by prokaryotic and eukaryotic DNA polymerases. Proc Natl Acad Sci USA 1981; 78:110–114.CrossRefGoogle Scholar
  3. 3.
    Armstrong JD, Kunz BA. Site and strand specificity of UVB mutagenesis in the SUP4-o gene of yeast. Proc Natl Acad Sci USA 1990; 87:9005–9009.CrossRefGoogle Scholar
  4. 4.
    Bohr VA, Smith CA, Okumoto DS et al. DNA repair in an active gene: removal of pyrimidine dimers from the DHFR gene of CHO cells is much more efficient than in the genome overall. Cell 1985; 40:359–369.CrossRefGoogle Scholar
  5. 5.
    Treiber DK, Zhai X, Jantzen H-M et al. Cisplatin-DNA adducts are molecular decoys for the ribosomal RNA transcription factor hUBF (human upstream binding factor). Proc Natl Acad Sci USA 1994; 91:5672–5676.CrossRefGoogle Scholar
  6. 6.
    MacLeod MC, Powell KL, Tran N. Binding of the transcription factor, Spl, to non-target sites in DNA modified by benzo[a]pyrene diol epoxide. Carcinogenesis 1995; 16:975–983.CrossRefGoogle Scholar
  7. 7.
    Turchi JJ, Henkels K. Human Ku autoantigen binds cisplatin-damaged DNA but fails to stimulate human DNA-activated protein kinase. J Biol Chem 1996; 271:13861–13867.CrossRefGoogle Scholar
  8. 8.
    Toney J, Donahue B, Kellett P et al. Isolation of cDNAs encoding a human protein that binds selectively to DNA modified by the anticancer drug cis-diamminedichloroplatinum. Proc Natl Acad Sci USA 1989; 86:8328–8332.CrossRefGoogle Scholar
  9. 9.
    Bruhn SL, Pil PM, Essigmann JM et al. Isolation and characterization of human cDNA clones encoding a high mobility group box protein that recognizes structural distortions to DNA caused by binding of the anticancer agent cisplatin. Proc Natl Acad Sci USA 1992; 89:2307–2311.CrossRefGoogle Scholar
  10. 10.
    Abrams MJ, Murrer BA. Metal compounds in therapy and diagnosis. Science 1993; 261:725–730.CrossRefGoogle Scholar
  11. 11.
    Andrews PA, Howell SB. Cellular pharmacology of cisplatin: perspectives on mechanisms of acquired resistance. Cancer Cells 1990; 2:35–43.Google Scholar
  12. 12.
    Pinto AL, Lippard SJ. Binding of the antitumor drug cis-diamminedichloroplatinum(II) (cisplatin) to DNA. Biochim Biophys Acta 1985; 780:167–180.Google Scholar
  13. 13.
    Eastman A. The formation, isolation and characterization of DNA adducts produced by anticancer platinum complexes. Pharmacol Ther 1987; 34:155–166.CrossRefGoogle Scholar
  14. 14.
    Howie JA, Gale GR. Cis-dichlorodiammineplatinum (II). Persistent and selective inhibition of deoxyribonucleic acid synthesis in vivo. Biochem Pharmacol 1970; 19:2757–2762.CrossRefGoogle Scholar
  15. 15.
    Ciccarelli RB, Solomon MJ, Varshavsky A et al. In vivo effects of cis-and trans-diamminedichloroplatinum(II) on SV40 chromosomes: differential repair, DNA-protein cross-linking, and inhibition of replication. Biochemistry 1985; 24:7533–7540.CrossRefGoogle Scholar
  16. 16.
    Barry MA, Behnke CA, Eastman A. Activation of programmed cell death (apoptosis) by cisplatin, other anticancer drugs, toxins and hyperthermia. Biochem Pharmacol 1990; 40:2353–2362.CrossRefGoogle Scholar
  17. 17.
    Eastman A. Activation of programmed cell death by anticancer agents: cisplatin as a model system. Cancer Cells 1990; 2:275–280.Google Scholar
  18. 18.
    Chu G. Cellular responses to cisplatin. J Biol Chem 1994; 269:787–790.Google Scholar
  19. 19.
    Pil PM, Lippard SJ. Specific binding of chromosomal protein HMG1 to DNA damaged by the anticancer drug cisplatin. Science 1992; 256:234–237.CrossRefGoogle Scholar
  20. 20.
    Hughes EN, Engelsberg BN, Billings PC. Purification of nuclear proteins that bind to cisplatin-damaged DNA. Identity with high mobility group proteins 1 and 2. J Biol Chem 1992; 267:13520–13527.Google Scholar
  21. 21.
    Brown SJ, Kellett PJ, Lippard SJ. Ixrl, a yeast protein that binds to platinated DNA and confers sensitivity to cisplatin. Science 1993; 261:603–605.CrossRefGoogle Scholar
  22. 22.
    Jantzen HM, Admon A, Bell SP et al. Nuclear transcription factor hUBF contains a DNA-binding motif with homology to HMG proteins. Nature 1990; 344:830–836.CrossRefGoogle Scholar
  23. 23.
    Lilley DM. DNA-protein interactions. HMG has DNA wrapped up. Nature 1992; 357:282–283.CrossRefGoogle Scholar
  24. 24.
    Bianchi ME, Falciola L, Ferrari S et al. The DNA binding site of HMG1 protein is composed of two similar segments (HMG boxes), both of which have counterparts in other eukaryotic regulatory sequences. EMBO J 1992; 11:1055–1063.Google Scholar
  25. 25.
    McA’Nulty MM, Whitehead JP, Lippard SJ. Binding of Ixrl, a yeast HMG-domain protein, to cisplatin-DNA adducts in vitro and in vivo. Biochemistry 1996; 362:75–86.Google Scholar
  26. 26.
    McA’Nulty MM, Lippard SJ. The HMG-domain protein Ixrl blocks excision repair of cisplatin-DNA adducts in yeast. Mutat Res 1996; 362:75–86.CrossRefGoogle Scholar
  27. 27.
    Huang J-C, Zambie DB, Reardon JT et al. HMG-domain proteins specifically inhibit the repair of the major DNA ad-duct of the anticancer drug cisplatin by human excision nuclease. Proc Natl Acad Sci USA 1994; 91:10394–10398.CrossRefGoogle Scholar
  28. 28.
    Zambie DB, Mu D, Reardon JT et al. Repair of cisplatin-DNA adducts by the mammalian excision nuclease. Biochemistry 1996; 35:10004–10013.CrossRefGoogle Scholar
  29. 29.
    Takahara PM, Rosenzweig AC, Frederick CA et al. Crystal structure of doublestranded DNA containing the major adduct of the anticancer drug cisplatin. Nature 1995; 377:649–652.CrossRefGoogle Scholar
  30. 30.
    den Hartog JH, Altona C, van Boom JH et al. Cis-diamminedichloroplatinum(II) induced distortion of a single and double stranded deoxydecanucleosideenona-phosphate studied by nuclear magnetic resonance. J Biomol Struct Dyn 1985; 2:1137–1155.CrossRefGoogle Scholar
  31. 31.
    Rice JA, Crothers DM, Pinto AL et al. The major adduct of the antitumor drug cis-diamminedichloroplatinum(II) with DNA bends the duplex by ≈40° toward the major groove. Proc Natl Acad Sci USA 1988; 85:4158–4161.CrossRefGoogle Scholar
  32. 32.
    Bellon SF, Lippard SJ. Bending studies of DNA site-specifically modified by cisplatin, trans-diamminedichloroplatinum(II) and cis-[Pt(NH3)2(N 3-cytosine)Cl]+. Biophys Chem 1990; 35:179–188.CrossRefGoogle Scholar
  33. 33.
    Bianchi ME, Beltrame M, Paonessa G. Specific recognition of cruciform DNA by nuclear protein HMG1. Science 1989; 243:1056–1059.CrossRefGoogle Scholar
  34. 34.
    Shirakata M, Hüppi K, Usuda S et al. HMGl-related DNA-binding protein isolated with V-(D)-J recombination signal probes. Mol Cell Biol 1991; 11:4528–4536.Google Scholar
  35. 35.
    King C-Y, Weiss MA. The SRY highmobility-group box recognizes DNA by partial intercalation in the minor groove: a topological mechanism of sequence specificity. Proc Natl Acad Sci USA 1993; 90:11990–11994.CrossRefGoogle Scholar
  36. 36.
    Gidoni D, Dynan WS, Tjian R. Multiple specific contacts between a mammalian transcription factor and its cognate promoter. Nature 1984; 312:409–413.CrossRefGoogle Scholar
  37. 37.
    Kadonaga JT, Jones KA, Tjian R. Promoter-specific activation of RNA polymerase II transcription by Spl. Trends Biochem Sci 1986; 11:20–23.CrossRefGoogle Scholar
  38. 38.
    MacLeod MC, Powell KL, Tran N. Binding of the transcription factor, Spl, to non-target sites in DNA modified by benzo[a]pyrene. Carcinogenesis 1995; 16:975–983.CrossRefGoogle Scholar
  39. 39.
    Sun D, Hurley LH. Cooperative bending of the 21-base-pair repeats of the SV40 viral early promoter by human Spl. Bio chemistry 1994; 33:9578–9587.Google Scholar
  40. 40.
    Gottlieb TM, Jackson SP. The DNA-dependent protein kinase: requirement for DNA ends and association with Ku antigen. Cell 1993; 72:131–142.CrossRefGoogle Scholar
  41. 41.
    Gottlieb TM, Jackson SP. Protein kinases and DNA damage. Trends Biochem Sci 1994; 19:500–503.CrossRefGoogle Scholar
  42. 42.
    Mimori T, Hardin JA. Mechanism of interaction between Ku protein and DNA. J Biol Chem 1986; 261:10375–10379.Google Scholar
  43. 43.
    Tuteja N, Tuteja R, Ochem A et al. Human DNA helicase II: a novel DNA unwinding enzyme identified as the Ku autoantigen. EMBO J 1994; 13:4991–5001.Google Scholar
  44. 44.
    Taccioli GE, Gottlieb TM, Blunt T et al. Ku80: product of the XRCC5 gene and its role in DNA repair and V(D)J recombination. Science 1994; 265:1442–1445.CrossRefGoogle Scholar
  45. 45.
    Smider V, Rathmell WK, Lieber MR et al. Restoration of X-ray resistance and V(D)J recombination in mutant cells by Ku cDNA. Science 1994; 266:289–291.CrossRefGoogle Scholar
  46. 46.
    Boubnov NV, Hall KT, Wills Z et al. Complementation of the ionizing radiation sensitivity, DNA end binding, and V(D)J recombination defects of doublestrand break repair mutants by the p86 Ku autoantigen. Proc Natl Acad Sci USA 1995; 92:890–894.CrossRefGoogle Scholar
  47. 47.
    Getts RC, Stamato TD. Absence of a Kulike DNA end binding activity in the xrs double-strand DNA repair-deficient mutant. J Biol Chem 1995; 269:15981–15984.Google Scholar
  48. 48.
    Thompson LH, Jeggo PA. Nomenclature of human genes involved in ionizing radiation sensitivity. Mutat Res 1995; 337:131–134.CrossRefGoogle Scholar
  49. 49.
    Mimori TY, Ohosone N, Hama A et al. Isolation and characterization of cDNA encoding the 80 kDa subunit protein of the human autoantigen Ku (p70/p80) recognized by autoantibodies from patients with skleroderma-polymyositis overlap syndrome. Proc Natl Acad Sci USA 1990; 87:1777–1781.CrossRefGoogle Scholar
  50. 50.
    Reeves WH, Sthoeger ZM. Molecular cloning of cDNA encoding the p70 (Ku) lupus autoantigen. J Biol Chem 1989; 264:5047–5052.Google Scholar
  51. 51.
    Sipley JD, Menninger JC, Hartley KO et al. Gene for the catalytic subunit of the human DNA-activated protein kinase maps to the site of the XRCC7 gene on chromosome 8. Proc Natl Acad Sci USA 1995; 92:7515–7519.CrossRefGoogle Scholar
  52. 52.
    Blunt T, Finnie NJ, Taccioli GE et al. Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine scid mutation. Cell 1995; 80:813–823.CrossRefGoogle Scholar
  53. 53.
    Kirchgessner CU, Patil CK, Evans JW et al. DNA dependent kinase (p350) as a candidate gene for the murine SCID defect. Science 1995; 267:1178–1182.CrossRefGoogle Scholar
  54. 54.
    Miller RD, Hogg J, Ozaki JH et al. Gene for the catalytic subunit of mouse DNA-dependent protein kinase maps to the scid locus. Proc Natl Acad Sci USA 1995; 92:10792–10795.CrossRefGoogle Scholar
  55. 55.
    Peterson SR, Kurimasa A, Oshimura M et al. Loss of the catalytic subunit of the DNA-dependent protein kinase in DNA double-strand-break-repair mutant mammalian cells. Proc Natl Acad Sci USA 1995; 92:3171–3174.CrossRefGoogle Scholar
  56. 56.
    Schuler W, Weiler IJ, Schuler A et al. Rearrangement of antigen receptor genes is defective in mice with severe combined immune deficiency. Cell 1986; 46:963–972.CrossRefGoogle Scholar
  57. 57.
    Biedermann KA, Sung J, Giaccia AJ et al. Scid mutation in mice confers hypersen-sitivity to ionizing radiation and a deficiency in DNA double-strand break repair. Proc Natl Acad Sci USA 1991; 88:1394–1397.CrossRefGoogle Scholar
  58. 58.
    Hendrickson EA, Qin XQ, Bump EA et al. A link between double-strand break-related repair and V(D)J recombination: the scid mutation. Proc Natl Acad Sci USA 1991; 88:4061–4065.CrossRefGoogle Scholar
  59. 59.
    Taccioli GE, Rathbun G, Oltz E et al. Impairment of V(D)J recombination in double-strand break repair mutants. Science 1993; 260:207–210.CrossRefGoogle Scholar
  60. 60.
    Anderson CW. DNA damage and the DNA-activated protein kinase. Trends Biochem Sci 1993; 18:433–437.CrossRefGoogle Scholar
  61. 61.
    Drummond JT, Li G-M, Longley MJ et al. Isolation of an hMSH2-pl60 heterodimer that restores DNA mismatch repair to tumor cells. Science 1995; 268:1909–1912.CrossRefGoogle Scholar
  62. 62.
    Palombo F, Gallinari P, Iaccarino I et al. GTBP, a 160-kilodalton protein essential for mismatch binding activity in human cells. Science 1995; 268:1912–1914.CrossRefGoogle Scholar
  63. 63.
    Duckett DR, Drummond JT, Murchie AIH et al. Human MutSα recognizes damaged DNA base pairs containing O 6-methylguanine, O 4-methylthymine, or the cisplatin-d(GpG) adduct. Proc Natl Acad Sci USA 1996; 93:6443–6447.CrossRefGoogle Scholar
  64. 64.
    Kat A, Thilly WG, Fang WH et al. An alkylation-tolerant, mutator human cell line is deficient in strand-specific mismatch repair. Proc Natl Acad Sci USA 1993; 90:6424–6428.CrossRefGoogle Scholar
  65. 65.
    Branch P, Aquilina G, Bignami M et al. Defective mismatch binding and a mutator phenotype in cells tolerant to DNA damage. Nature 1993; 362:652–654.CrossRefGoogle Scholar
  66. 66.
    Hearst JE. The structure of photolyase: using photon energy for DNA repair. Science 1995; 268:1859–1859.CrossRefGoogle Scholar
  67. 67.
    Kim ST, Sancar A. Photochemistry, photophysics, and mechanism of pyrimidine dimer repair by DNA photolyase. Photochem Photobiol 1993; 57:895–904.CrossRefGoogle Scholar
  68. 68.
    Yamamoto K, Satake M, Shinigawa H et al. Amelioration of the ultraviolet sensitivity of an Escherichia coli RecA mutant in the dark by photoreactivating enzyme. Mol Gen Genet 1983; 190:511–515.CrossRefGoogle Scholar
  69. 69.
    Sancar A, Franklin KA, Sancar GB. Escherichia coli DNA photolyase stimulates UvrABC excision nuclease in vitro. Proc Natl Acad Sci USA 1984; 81:7397–7401.CrossRefGoogle Scholar
  70. 70.
    Sancar GB, Smith FW. Interactions between yeast photolyase and nucleotide excision repair proteins in Saccharomyces cerevisiae and Escherichia coli. Mol Cell Biol 1989; 9:4767–4776.Google Scholar
  71. 71.
    Sancar A, Tang M-S. Nucleotide excision repair. Photochem Photobiol 1993; 57:905–921.CrossRefGoogle Scholar
  72. 72.
    Fox ME, Feldman BJ, Chu G. A novel role for DNA photolyase: binding to DNA damaged by drugs is associated with enhanced cytotoxicity in Saccharomyces cerevisiae. Mol Cell Biol 1994; 14:8071–8077.Google Scholar
  73. 73.
    Özer Z, Reardon JT, Hsu DS et al. The other function of DNA photolyase: stimulation of excision repair of chemical damage to DNA. Biochemistry 1995; 34:15886–15889.CrossRefGoogle Scholar

Copyright information

© R.G. Landes Company 1997

Authors and Affiliations

  • Hanspeter Naegeli
    • 1
  1. 1.Institute of Pharmacology and ToxicologyUniversity of Zürich-TierspitalZürichSwitzerland

Personalised recommendations