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Journal of Nucleic Acids
Volume 2010, Article ID 543531, 7 pages
http://dx.doi.org/10.4061/2010/543531
Review Article

DNA Damage Induced by Alkylating Agents and Repair Pathways

1Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, Kumatori-cho, Sennan-gun, Osaka 590-0494, Japan
2Department of Biology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan
3Department of Radiation Oncology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan

Received 8 June 2010; Revised 26 August 2010; Accepted 12 October 2010

Academic Editor: Ashis Basu

Copyright © 2010 Natsuko Kondo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. S. G. Chaney and A. Sancar, “DNA repair: enzymatic mechanisms and relevance to drug response,” Journal of the National Cancer Institute, vol. 88, no. 19, pp. 1346–1360, 1996. View at Google Scholar · View at Scopus
  2. D. T. Beranek, “Distribution of methyl and ethyl adducts following alkylation with monofunctional alkylating agents,” Mutation Research, vol. 231, no. 1, pp. 11–30, 1990. View at Google Scholar · View at Scopus
  3. R. Goth and M. F. Rajewsky, “Persistence of O6 ethylguanine in rat brain DNA: correlation with nervous system specific carcinogenesis by ethylnitrosourea,” Proceedings of the National Academy of Sciences of the United States of America, vol. 71, no. 3, pp. 639–643, 1974. View at Google Scholar · View at Scopus
  4. R. Goth-Goldstein, “Inability of Chinese hamster ovary cells to excise O6-alkylguanine,” Cancer Research, vol. 40, no. 7, pp. 2623–2624, 1980. View at Google Scholar · View at Scopus
  5. B. Kaina, A. A. van Zeeland, A. de Groot, and A. T. Natarajan, “DNA repair and chromosomal stability in the alkylating agent-hypersensitive Chinese hamster cell line 27-1,” Mutation Research, vol. 243, no. 3, pp. 219–224, 1990. View at Google Scholar · View at Scopus
  6. G. P. Margison, M. F. Santibáñez-Koref, and A. C. Povey, “Mechanisms of carcinogenicity/chemotherapy by O6-methylguanine,” Mutagenesis, vol. 17, no. 6, pp. 483–487, 2002. View at Google Scholar · View at Scopus
  7. M. Christmann, M. T. Tomicic, W. P. Roos, and B. Kaina, “Mechanisms of human DNA repair: an update,” Toxicology, vol. 193, no. 1-2, pp. 3–34, 2003. View at Publisher · View at Google Scholar · View at Scopus
  8. M. D. Wyatt, J. M. Allan, A. Y. Lau, T. E. Ellenberger, and L. D. Samson, “3-Methyladenine DNA glycosylases: structure, function, and biological importance,” BioEssays, vol. 21, no. 8, pp. 668–676, 1999. View at Google Scholar · View at Scopus
  9. H. E. Krokan, R. Standal, and G. Slupphaug, “DNA glycosylases in the base excision repair of DNA,” Biochemical Journal, vol. 325, no. 1, pp. 1–16, 1997. View at Google Scholar · View at Scopus
  10. B. Kaina, M. Christmann, S. Naumann, and W. P. Roos, “MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents,” DNA Repair, vol. 6, no. 8, pp. 1079–1099, 2007. View at Publisher · View at Google Scholar · View at Scopus
  11. A. Sancar, “Excision repair in mammalian cells,” The Journal of Biological Chemistry, vol. 270, no. 27, pp. 15915–15918, 1995. View at Google Scholar · View at Scopus
  12. H. T. Chen, A. Bhandoola, M. J. Difilippantonio et al., “Response to RAG-mediated V(D)J cleavage by NBS1 and γ-H2AX,” Science, vol. 290, no. 5498, pp. 1962–1964, 2000. View at Publisher · View at Google Scholar · View at Scopus
  13. G. P. Margison and M. F. Santibáñez-Koref, “O6-alkylguanine-DNA alkyltransferase: role in carcinogenesis and chemotherapy,” BioEssays, vol. 24, no. 3, pp. 255–266, 2002. View at Publisher · View at Google Scholar · View at Scopus
  14. W. P. Roos, T. Nikolova, S. Quiros et al., “Brca2/Xrcc2 dependent HR, but not NHEJ, is required for protection against O6-methylguanine triggered apoptosis, DSBs and chromosomal aberrations by a process leading to SCEs,” DNA Repair, vol. 8, no. 1, pp. 72–86, 2009. View at Publisher · View at Google Scholar · View at Scopus
  15. N. Kondo, A. Takahashi, E. Mori et al., “DNA ligase IV as a new molecular target for temozolomide,” Biochemical and Biophysical Research Communications, vol. 387, no. 4, pp. 656–660, 2009. View at Publisher · View at Google Scholar · View at Scopus
  16. F. Drabløs, E. Feyzi, P. A. Aas et al., “Alkylation damage in DNA and RNA—repair mechanisms and medical significance,” DNA Repair, vol. 3, no. 11, pp. 1389–1407, 2004. View at Publisher · View at Google Scholar · View at Scopus
  17. R. S. Day III, C. H. J. Ziolkowski, and D. A. Scudiero, “Defective repair of alkylated DNA by human tumour and SV40-transformed human cell strains,” Nature, vol. 288, no. 5792, pp. 724–727, 1980. View at Google Scholar · View at Scopus
  18. N. Hosoya and K. Miyagawa, “Clinical importance of DNA repair inhibitors in cancer therapy,” Memo—Magazine of European Medical Oncology, vol. 2, no. 1, pp. 9–14, 2009. View at Publisher · View at Google Scholar
  19. M. D. Blough, M. C. Zlatescu, and J. G. Cairncross, “O6-methylguanine-DNA methyltransferase regulation by p53 in astrocytic cells,” Cancer Research, vol. 67, no. 2, pp. 580–584, 2007. View at Publisher · View at Google Scholar · View at Scopus
  20. S. J. Russell, Y.-W. Ye, P. G. Waber, M. Shuford, S. C. Schold Jr., and P. D. Nisen, “p53 Mutations, O6-alkylguanine DNA alkyltransferase activity, and sensitivity to procarbazine in human brain tumors,” Cancer, vol. 75, no. 6, pp. 1339–1342, 1995. View at Google Scholar · View at Scopus
  21. M. Esteller, S. R. Hamilton, P. C. Burger, S. B. Baylin, and J. G. Herman, “Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia,” Cancer Research, vol. 59, no. 4, pp. 793–797, 1999. View at Google Scholar · View at Scopus
  22. I. Preuss, I. Eberhagen, S. Haas et al., “O6-methylguanine-DNA methyltransferase activity in breast and brain tumors,” International Journal of Cancer, vol. 61, no. 3, pp. 321–326, 1995. View at Google Scholar · View at Scopus
  23. N. P. Lees, K. L. Harrison, E. Hill, C. Nicholas Hall, A. C. Povey, and G. P. Margison, “Heterogeneity of O6-alkylguanine-DNA alkyltransferase activity in colorectal cancer: implications for treatment,” Oncology, vol. 63, no. 4, pp. 393–397, 2002. View at Publisher · View at Google Scholar · View at Scopus
  24. P. Karran, “Mechanisms of tolerance to DNA damaging therapeutic drugs,” Carcinogenesis, vol. 22, no. 12, pp. 1931–1937, 2001. View at Google Scholar · View at Scopus
  25. L. Stojic, R. Brun, and J. Jiricny, “Mismatch repair and DNA damage signalling,” DNA Repair, vol. 3, no. 8-9, pp. 1091–1101, 2004. View at Publisher · View at Google Scholar · View at Scopus
  26. P. Branch, G. Aquilina, M. Bignami, and P. Karran, “Defective mismatch binding and a mutator phenotype in cells tolerant to DNA damage,” Nature, vol. 362, no. 6421, pp. 652–654, 1993. View at Publisher · View at Google Scholar · View at Scopus
  27. A. Kat, W. G. Thilly, W.-H. Fang, M. J. Longley, G.-M. Li, and P. Modrich, “An alkylation-tolerant, mutator human cell line is deficient in strand- specific mismatch repair,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 14, pp. 6424–6428, 1993. View at Google Scholar · View at Scopus
  28. S. Quiros, W. P. Roos, and B. Kaina, “Processing of O6-methylguanine into DNA double-strand breaks requires two rounds of replication whereas apoptosis is also induced in subsequent cell cycles,” Cell Cycle, vol. 9, no. 1, pp. 168–178, 2010. View at Google Scholar
  29. N. Kondo, A. Takahashi, E. Mori et al., “DNA ligase IV is a potential molecular target in ACNU sensitivity,” Cancer Science, vol. 101, no. 8, pp. 1881–1885, 2010. View at Publisher · View at Google Scholar
  30. S. C. Naumann, W. P. Roos, E. Jöst et al., “Temozolomide- and fotemustine-induced apoptosis in human malignant melanoma cells: response related to MGMT, MMR, DSBs, and p53,” British Journal of Cancer, vol. 100, no. 2, pp. 322–333, 2009. View at Publisher · View at Google Scholar · View at Scopus
  31. T. Ohnishi, E. Mori, and A. Takahashi, “DNA double-strand breaks: their production, recognition, and repair in eukaryotes,” Mutation Research, vol. 669, no. 1-2, pp. 8–12, 2009. View at Publisher · View at Google Scholar · View at Scopus
  32. A. A. Davies, J. Y. Masson, M. J. McIlwraith et al., “Role of BRCA2 in control of the RAD51 recombination and DNA repair protein,” Molecular Cell, vol. 7, no. 2, pp. 273–282, 2001. View at Publisher · View at Google Scholar · View at Scopus
  33. N. Mojas, M. Lopes, and J. Jiricny, “Mismatch repair-dependent processing of methylation damage gives rise to persistent single-stranded gaps in newly replicated DNA,” Genes and Development, vol. 21, no. 24, pp. 3342–3355, 2007. View at Publisher · View at Google Scholar · View at Scopus
  34. T. Helleday, J. Lo, D. C. van Gent, and B. P. Engelward, “DNA double-strand break repair: from mechanistic understanding to cancer treatment,” DNA Repair, vol. 6, no. 7, pp. 923–935, 2007. View at Publisher · View at Google Scholar · View at Scopus
  35. R. W. Sobol and S. H. Wilson, “Mammalian DNA β-polymerase in base excision repair of alkylation damage,” Progress in Nucleic Acid Research and Molecular Biology, vol. 68, pp. 57–74, 2001. View at Google Scholar · View at Scopus
  36. S. H. Wilson, R. W. Sobol, W. A. Beard, J. K. Horton, R. Prasad, and B. J. Vande Berg, “DNA polymerase β and mammalian base excision repair,” Cold Spring Harbor Symposia on Quantitative Biology, vol. 65, pp. 143–155, 2000. View at Google Scholar · View at Scopus
  37. R. W. Sobol, J. K. Horton, R. Kühn et al., “Requirement of mammalian DNA polymerase-β in base-excision repair,” Nature, vol. 379, no. 6561, pp. 183–186, 1996. View at Publisher · View at Google Scholar · View at Scopus
  38. R. W. Sobol, R. Prasad, A. Evenski et al., “The lyase activity of the DNA repair protein β-polymerase protects from DNA-damage-induced cytotoxicity,” Nature, vol. 405, no. 6788, pp. 807–810, 2000. View at Publisher · View at Google Scholar · View at Scopus
  39. R. Prasad, K. Bebenek, E. Hou et al., “Localization of the deoxyribose phosphate lyase active site in human DNA polymerase β by controlled proteolysis,” The Journal of Biological Chemistry, vol. 278, no. 32, pp. 29649–29654, 2003. View at Publisher · View at Google Scholar · View at Scopus
  40. K. Bebenek, A. Tissier, E. G. Frank et al., “5-deoxyribose phosphate lyase activity of human DNA polymerase L in vitro,” Science, vol. 291, no. 5511, pp. 2156–2159, 2001. View at Publisher · View at Google Scholar · View at Scopus
  41. M. García-Díaz, K. Bebenek, T. A. Kunkel, and L. Blanco, “Identification of an intrinsic 5-deoxyribose-5-phosphate lyase activity in human DNA polymerase λ: a possible role in base excision repair,” The Journal of Biological Chemistry, vol. 276, no. 37, pp. 34659–34663, 2001. View at Publisher · View at Google Scholar · View at Scopus
  42. T. Lindahl and R. D. Wood, “Quality control by DNA repair,” Science, vol. 286, no. 5446, pp. 1897–1905, 1999. View at Publisher · View at Google Scholar · View at Scopus
  43. R. W. Sobolt, M. Kartalou, K. H. Almeida et al., “Base excision repair intermediates induce p53-independent cytotoxic and genotoxic responses,” The Journal of Biological Chemistry, vol. 278, no. 41, pp. 39951–39959, 2003. View at Publisher · View at Google Scholar · View at Scopus
  44. R. W. Sobol, D. E. Watson, J. Nakamura et al., “Mutations associated with base excision repair deficiency and methylation-induced genotoxic stress,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 10, pp. 6860–6865, 2002. View at Publisher · View at Google Scholar · View at Scopus
  45. J. K. Horton, D. F. Joyce-Gray, B. F. Pachkowski, J. A. Swenberg, and S. H. Wilson, “Hypersensitivity of DNA polymerase β null mouse fibroblasts reflects accumulation of cytotoxic repair intermediates from site-specific alkyl DNA lesions,” DNA Repair, vol. 2, no. 1, pp. 27–48, 2003. View at Publisher · View at Google Scholar · View at Scopus
  46. R. N. Trivedi, K. H. Almeida, J. L. Fornsaglio, S. Schamus, and R. W. Sobol, “The role of base excision repair in the sensitivity and resistance to temozolomide-mediated cell death,” Cancer Research, vol. 65, no. 14, pp. 6394–6400, 2005. View at Publisher · View at Google Scholar · View at Scopus
  47. E. P. Rogakou, D. R. Pilch, A. H. Orr, V. S. Ivanova, and W. M. Bonner, “DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139,” The Journal of Biological Chemistry, vol. 273, no. 10, pp. 5858–5868, 1998. View at Publisher · View at Google Scholar · View at Scopus
  48. I. M. Ward and J. Chen, “Histone H2AX is phosphorylated in an ATR-dependent manner in response to replicational stress,” The Journal of Biological Chemistry, vol. 276, no. 51, pp. 47759–47762, 2001. View at Google Scholar · View at Scopus
  49. N. J. Curtin, L.-Z. Wang, A. Yiakouvaki et al., “Novel poly(ADP-ribose) polymerase-1 inhibitor, AG14361, restores rensitivity to temozolomide in mismatch repair-deficient cells,” Clinical Cancer Research, vol. 10, no. 3, pp. 881–889, 2004. View at Publisher · View at Google Scholar · View at Scopus
  50. T. Duncan, S. C. Trewick, P. Koivisto, P. A. Bates, T. Lindahl, and B. Sedgwick, “Reversal of DNA alkylation damage by two human dioxygenases,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 26, pp. 16660–16665, 2002. View at Publisher · View at Google Scholar · View at Scopus
  51. P. A. Aas, M. Otterlei, P. O. Falnes et al., “Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA,” Nature, vol. 421, no. 6925, pp. 859–863, 2003. View at Publisher · View at Google Scholar · View at Scopus
  52. P. M. O'Connor and K. W. Kohn, “Comparative pharmacokinetics of DNA lesion formation and removal following treatment of L1210 cells with nitrogen mustards,” Cancer Communications, vol. 2, no. 12, pp. 387–394, 1990. View at Google Scholar · View at Scopus
  53. M. R. Middleton and G. P. Margison, “Improvement of chemotherapy efficacy by inactivation of a DNA-repair pathway,” Lancet Oncology, vol. 4, no. 1, pp. 37–44, 2003. View at Publisher · View at Google Scholar · View at Scopus
  54. L. H. Thompson and J. M. Hinz, “Cellular and molecular consequences of defective Fanconi anemia proteins in replication-coupled DNA repair: mechanistic insights,” Mutation Research, vol. 668, no. 1-2, pp. 54–72, 2009. View at Publisher · View at Google Scholar · View at Scopus
  55. K. Yamamoto, M. Ishiai, N. Matsushita et al., “Fanconi anemia FANCG protein in mitigating radiation- and enzyme-induced DNA double-strand breaks by homologous recombination in vertebrate cells,” Molecular and Cellular Biology, vol. 23, no. 15, pp. 5421–5430, 2003. View at Publisher · View at Google Scholar · View at Scopus
  56. K. Nakanishi, Y.-G. Yang, A. J. Pierce et al., “Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 4, pp. 1110–1115, 2005. View at Publisher · View at Google Scholar · View at Scopus
  57. A. R. Meetei, A. L. Medhurst, C. Ling et al., “A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M,” Nature Genetics, vol. 37, no. 9, pp. 958–963, 2005. View at Publisher · View at Google Scholar · View at Scopus
  58. A. Ciccia, C. Ling, R. Coulthard et al., “Identification of FAAP24, a Fanconi Anemia Core Complex Protein that Interacts with FANCM,” Molecular Cell, vol. 25, no. 3, pp. 331–343, 2007. View at Publisher · View at Google Scholar · View at Scopus
  59. Y. Masuda, M. Ohmae, K. Masuda, and K. Kamiya, “Structure and enzymatic properties of a stable complex of the human REV1 and REV7 proteins,” The Journal of Biological Chemistry, vol. 278, no. 14, pp. 12356–12360, 2003. View at Publisher · View at Google Scholar · View at Scopus
  60. M. L. G. Dronkert and R. Kanaar, “Repair of DNA interstrand cross-links,” Mutation Research, vol. 486, no. 4, pp. 217–247, 2001. View at Publisher · View at Google Scholar · View at Scopus
  61. M. E. Hegi, A.-C. Diserens, T. Gorlia et al., “MGMT gene silencing and benefit from temozolomide in glioblastoma,” The New England Journal of Medicine, vol. 352, no. 10, pp. 997–1003, 2005. View at Publisher · View at Google Scholar · View at Scopus
  62. M. Esteller, J. Garcia-Foncillas, E. Andion et al., “Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents,” The New England Journal of Medicine, vol. 343, no. 13, pp. 1350–1354, 2000. View at Publisher · View at Google Scholar · View at Scopus
  63. T. Helleday, E. Petermann, C. Lundin, B. Hodgson, and R. A. Sharma, “DNA repair pathways as targets for cancer therapy,” Nature Reviews Cancer, vol. 8, no. 3, pp. 193–204, 2008. View at Publisher · View at Google Scholar · View at Scopus
  64. J. A. Quinn, A. Desjardins, J. Weingart et al., “Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma,” Journal of Clinical Oncology, vol. 23, no. 28, pp. 7178–7187, 2005. View at Publisher · View at Google Scholar · View at Scopus
  65. O. Khan and M. R. Middleton, “The therapeutic potential of O6-alkylguanine DNA alkyltransferase inhibitors,” Expert Opinion on Investigational Drugs, vol. 16, no. 10, pp. 1573–1584, 2007. View at Publisher · View at Google Scholar · View at Scopus
  66. A. Giese, T. Kucinski, U. Knopp et al., “Pattern of recurrence following local chemotherapy with biodegradable carmustine (BCNU) implants in patients with glioblastoma,” Journal of Neuro-Oncology, vol. 66, no. 3, pp. 351–360, 2004. View at Publisher · View at Google Scholar · View at Scopus