Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Transcriptional mutagenesis: causes and involvement in tumour development

Nature Reviews Cancer volume 11, pages 218–227 (2011)Cite this article

Subjects

Abstract

The majority of human cells do not multiply continuously but are quiescent or slow-replicating and devote a large part of their energy to transcription. When DNA damage in the transcribed strand of an active gene is bypassed by a RNA polymerase, they can miscode at the damaged site and produce mutant transcripts. This process is known as transcriptional mutagenesis and, as discussed in this Perspective, could lead to the production of mutant proteins and might therefore be important in tumour development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: DNA replication-independent production of erroneous proteins.
Figure 2: The potential role of transcriptional mutagenesis in tumour development.

Similar content being viewed by others

References

  1. Weinberg, R. A. The Biology of Cancer (Garland Science, New York, 2006).

    Book  Google Scholar 

  2. Goodman, M. F. Error-prone repair DNA polymerases in prokaryotes and eukaryotes. Annu. Rev. Biochem. 71, 17–50 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Kunkel, T. A. & Bebenek, K. DNA replication fidelity. Annu. Rev. Biochem. 69, 497–529 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Friedberg, E. C. et al. DNA Repair and Mutagenesis (ASM Press, Washington DC, 2006).

    Google Scholar 

  5. Loeb, L. A. & Monnat, R. J. Jr. DNA polymerases and human disease. Nature Rev. Genet. 9, 594–604 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Nouspikel, T. & Hanawalt, P. C. DNA repair in terminally differentiated cells. DNA Repair (Amst.) 1, 59–75 (2002).

    Article  CAS  Google Scholar 

  7. Drummond, D. A. & Wilke, C. O. The evolutionary consequences of erroneous protein synthesis. Nature Rev. Genet. 10, 715–724 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Parker, J. Errors and alternatives in reading the universal genetic code. Microbiol. Rev. 53, 273–298 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fox-Walsh, K. L. & Hertel, K. J. Splice-site pairing is an intrinsically high fidelity process. Proc. Natl Acad. Sci. USA 106, 1766–1771 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Taipale, M., Jarosz, D. F. & Lindquist, S. HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nature Rev. Mol. Cell. Biol. 11, 515–528 (2010).

    Article  CAS  Google Scholar 

  11. Silvera, D., Formenti, S. C. & Schneider, R. J. Translational control in cancer. Nature Rev. Cancer 10, 254–266 (2010).

    Article  CAS  Google Scholar 

  12. Taddei, F. et al. Counteraction by MutT protein of transcriptional errors caused by oxidative damage. Science 278, 128–130 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. Bellacosa, A. & Moss, E. G. RNA repair: damage control. Curr. Biol. 13, R482–R484 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Brégeon, D. & Sarasin, A. Hypothetical role of RNA damage avoidance in preventing human disease. Mutat. Res. 577, 293–302 (2005).

    Article  PubMed  CAS  Google Scholar 

  15. Tanaka, M., Chock, P. B. & Stadtman, E. R. Oxidized messenger RNA induces translation errors. Proc. Natl Acad. Sci. USA 104, 66–71 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Kireeva, M. L. et al. Transient reversal of RNA polymerase II active site closing controls fidelity of transcription elongation. Mol. Cell 30, 557–566 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Remington, K. M., Bennett, S. E., Harris, C. M., Harris, T. M. & Bebenek, K. Highly mutagenic bypass synthesis by T7 RNA polymerase of site-specific benzo[a]pyrene diol epoxide-adducted template DNA. J. Biol. Chem. 273, 13170–13176 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Shaw, R. J., Bonawitz, N. D. & Reines, D. Use of an in vivo reporter assay to test for transcriptional and translational fidelity in yeast. J. Biol. Chem. 277, 24420–24426 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Blank, A., Gallant, J. A., Burgess, R. R. & Loeb, L. A. An RNA polymerase mutant with reduced accuracy of chain elongation. Biochemistry 25, 5920–5928 (1986).

    Article  CAS  PubMed  Google Scholar 

  20. Brakier-Gingras, L. & Phoenix, P. The control of accuracy during protein synthesis in Escherichia coli and perturbations of this control by streptomycin, neomycin, or ribosomal mutations. Can. J. Biochem. Cell. Biol. 62, 231–244 (1984).

    Article  CAS  PubMed  Google Scholar 

  21. Nangle, L. A., Motta, C. M. & Schimmel, P. Global effects of mistranslation from an editing defect in mammalian cells. Chem. Biol. 13, 1091–1100 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Bacher, J. M., de Crecy-Lagard, V. & Schimmel, P. R. Inhibited cell growth and protein functional changes from an editing-defective tRNA synthetase. Proc. Natl Acad. Sci. USA 102, 1697–1701 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Goldsmith, M. & Tawfik, D. S. Potential role of phenotypic mutations in the evolution of protein expression and stability. Proc. Natl Acad. Sci. USA 106, 6197–6202 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Liu, J., Zhou, W. & Doetsch, P. W. RNA polymerase bypass at sites of dihydrouracil: implications for transcriptional mutagenesis. Mol. Cell. Biol. 15, 6729–6735 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. You, H. J., Viswanathan, A. & Doetsch, P. W. In vivo technique for determining transcriptional mutagenesis. Methods 22, 120–126 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Zhou, W. & Doetsch, P. W. in Microbial Genome Methods (ed. Adolph, K. W.) 151–165 (CRC Press, Boca Raton, 1996).

    Google Scholar 

  27. Brégeon, D. & Doetsch, P. W. Reliable method for generating double-stranded DNA vectors containing site-specific base modifications. Biotechniques 37, 760–766 (2004).

    Article  PubMed  Google Scholar 

  28. Brégeon, D. & Doetsch, P. W. Assays for transcriptional mutagenesis in active genes. Methods Enzymol. 409, 345–357 (2006).

    Article  PubMed  CAS  Google Scholar 

  29. Viswanathan, A., You, H. J. & Doetsch, P. W. Phenotypic change caused by transcriptional bypass of uracil in nondividing cells. Science 284, 159–162 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Brégeon, D., Doddridge, Z. A., You, H. J., Weiss, B. & Doetsch, P. W. Transcriptional mutagenesis induced by uracil and 8-oxoguanine in Escherichia coli. Mol. Cell 12, 959–970 (2003).

    Article  PubMed  Google Scholar 

  31. Clauson, C. L., Oestreich, K. J., Austin, J. W. & Doetsch, P. W. Abasic sites and strand breaks in DNA cause transcriptional mutagenesis in Escherichia coli. Proc. Natl Acad. Sci. USA 107, 3657–3662 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Brégeon, D., Peignon, P. A. & Sarasin, A. Transcriptional mutagenesis induced by 8-oxoguanine in mammalian cells. PLoS Genet. 5, e1000577 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Marietta, C. & Brooks, P. J. Transcriptional bypass of bulky DNA lesions causes new mutant RNA transcripts in human cells. EMBO Rep. 8, 388–393 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Saxowsky, T. T., Meadows, K. L., Klungland, A. & Doetsch, P. W. 8-Oxoguanine-mediated transcriptional mutagenesis causes Ras activation in mammalian cells. Proc. Natl Acad. Sci. USA 105, 18877–18882 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. De Bont, R. & van Larebeke, N. Endogenous DNA damage in humans: a review of quantitative data. Mutagenesis 19, 169–185 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. van Loon, B., Markkanen, E. & Hubscher, U. Oxygen as a friend and enemy: how to combat the mutational potential of 8-oxo-guanine. DNA Repair (Amst.) 9, 604–616 (2010).

    Article  CAS  Google Scholar 

  37. Hanawalt, P. C. & Spivak, G. Transcription-coupled DNA repair: two decades of progress and surprises. Nature Rev. Mol. Cell. Biol. 9, 958–970 (2008).

    Article  CAS  Google Scholar 

  38. Tornaletti, S. DNA repair in mammalian cells: transcription-coupled DNA repair: directing your effort where it's most needed. Cell. Mol. Life Sci. 66, 1010–1020 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Doetsch, P. W. Translesion synthesis by RNA polymerases: occurrence and biological implications for transcriptional mutagenesis. Mutat. Res. 510, 131–140 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Saxowsky, T. T. & Doetsch, P. W. RNA polymerase encounters with DNA damage: transcription-coupled repair or transcriptional mutagenesis? Chem. Rev. 106, 474–488 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Kuraoka, I. et al. Effects of endogenous DNA base lesions on transcription elongation by mammalian RNA polymerase II. Implications for transcription-coupled DNA repair and transcriptional mutagenesis. J. Biol. Chem. 278, 7294–7299 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Liu, J. & Doetsch, P. W. Escherichia coli RNA and DNA polymerase bypass of dihydrouracil: mutagenic potential via transcription and replication. Nucleic Acids Res. 26, 1707–1712 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Viswanathan, A. & Doetsch, P. W. Effects of nonbulky DNA base damages on Escherichia coli RNA polymerase-mediated elongation and promoter clearance. J. Biol. Chem. 273, 21276–21281 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Zhou, W. & Doetsch, P. W. Effects of abasic sites and DNA single-strand breaks on prokaryotic RNA polymerases. Proc. Natl Acad. Sci. USA 90, 6601–6605 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhou, W. & Doetsch, P. W. Transcription bypass or blockage at single-strand breaks on the DNA template strand: effect of different 3′ and 5′ flanking groups on the T7 RNA polymerase elongation complex. Biochemistry 33, 14926–14934 (1994).

    Article  CAS  PubMed  Google Scholar 

  46. Zhou, W. & Doetsch, P. W. Efficient bypass and base misinsertions at abasic sites by prokaryotic RNA polymerases. Ann. N. Y. Acad. Sci. 726, 351–354 (1994).

    Article  CAS  PubMed  Google Scholar 

  47. Kuraoka, I. et al. Removal of oxygen free-radical-induced 5′, 8-purine cyclodeoxynucleosides from DNA by the nucleotide excision-repair pathway in human cells. Proc. Natl Acad. Sci. USA 97, 3832–3837 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Galli, F. et al. Oxidative stress and reactive oxygen species. Contrib. Nephrol. 149, 240–260 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Sedelnikova, O. A. et al. Role of oxidatively induced DNA lesions in human pathogenesis. Mutat. Res. 704, 152–159 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Barnes, D. E. & Lindahl, T. Repair and genetic consequences of endogenous DNA base damage in mammalian cells. Annu. Rev. Genet. 38, 445–476 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Charlet-Berguerand, N. et al. RNA polymerase II bypass of oxidative DNA damage is regulated by transcription elongation factors. EMBO J. 25, 5481–5491 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Htun, H. & Johnston, B. H. Mapping adducts of DNA structural probes using transcription and primer extension approaches. Methods Enzymol. 212, 272–294 (1992).

    Article  CAS  PubMed  Google Scholar 

  53. Tornaletti, S., Maeda, L. S., Lloyd, D. R., Reines, D. & Hanawalt, P. C. Effect of thymine glycol on transcription elongation by T7 RNA polymerase and mammalian RNA polymerase II. J. Biol. Chem. 276, 45367–45371 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Dimitri, A. et al. Transcription of DNA containing the 5-guanidino-4-nitroimidazole lesion by human RNA polymerase II and bacteriophage T7 RNA polymerase. DNA Repair (Amst.) 7, 1276–1288 (2008).

    Article  CAS  Google Scholar 

  55. Chen, Y. H. & Bogenhagen, D. F. Effects of DNA lesions on transcription elongation by T7 RNA polymerase. J. Biol. Chem. 268, 5849–5855 (1993).

    Article  CAS  PubMed  Google Scholar 

  56. Olinski, R., Gackowski, D., Rozalski, R., Foksinski, M. & Bialkowski, K. Oxidative DNA damage in cancer patients: a cause or a consequence of the disease development? Mutat. Res. 531, 177–190 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Damsma, G. E. & Cramer, P. Molecular basis of transcriptional mutagenesis at 8-oxoguanine. J. Biol. Chem. 284, 31658–31663 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Cheng, K. C., Cahill, D. S., Kasai, H., Nishimura, S. & Loeb, L. A. 8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G→T and A→C substitutions. J. Biol. Chem. 267, 166–172 (1992).

    Article  CAS  PubMed  Google Scholar 

  59. Moriya, M. et al. Site-specific mutagenesis using a gapped duplex vector: a study of translesion synthesis past 8-oxodeoxyguanosine in E. coli. Mutat. Res. 254, 281–288 (1991).

    Article  CAS  PubMed  Google Scholar 

  60. Shibutani, S., Margulis, L. A., Geacintov, N. E. & Grollman, A. P. Translesional synthesis on a DNA template containing a single stereoisomer of dG-(+)- or dG-(-)-anti-BPDE (7,8-dihydroxy-anti-9,10-epoxy-7, 8,9,10-tetrahydrobenzo[a]pyrene). Biochemistry 32, 7531–7541 (1993).

    Article  CAS  PubMed  Google Scholar 

  61. Singer, B. & Dosanjh, M. K. Site-directed mutagenesis for quantitation of base-base interactions at defined sites. Mutat. Res. 233, 45–51 (1990).

    Article  CAS  PubMed  Google Scholar 

  62. Wood, M. L., Dizdaroglu, M., Gajewski, E. & Essigmann, J. M. 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. Biochemistry 29, 7024–7032 (1990).

    Article  CAS  PubMed  Google Scholar 

  63. Wood, M. L., Esteve, A., Morningstar, M. L., Kuziemko, G. M. & Essigmann, J. M. Genetic effects of oxidative DNA damage: comparative mutagenesis of 7, 8-dihydro-8-oxoguanine and 7, 8-dihydro-8-oxoadenine in Escherichia coli. Nucleic Acids Res. 20, 6023–6032 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hsu, G. W., Ober, M., Carell, T. & Beese, L. S. Error-prone replication of oxidatively damaged DNA by a high-fidelity DNA polymerase. Nature 431, 217–221 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Kouchakdjian, M. et al. NMR structural studies of the ionizing radiation adduct 7-hydro-8-oxodeoxyguanosine (8-oxo-7H-dG) opposite deoxyadenosine in a DNA duplex. 8-Oxo-7H-dG(syn).dA(anti) alignment at lesion site. Biochemistry 30, 1403–1412 (1991).

    Article  CAS  PubMed  Google Scholar 

  66. Brooks, P. J. et al. The oxidative DNA lesion 8,5′-(S)-cyclo-2′-deoxyadenosine is repaired by the nucleotide excision repair pathway and blocks gene expression in mammalian cells. J. Biol. Chem. 275, 22355–22362 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. Damsma, G. E., Alt, A., Brueckner, F., Carell, T. & Cramer, P. Mechanism of transcriptional stalling at cisplatin-damaged DNA. Nature Struct. Mol. Biol. 14, 1127–1133 (2007).

    Article  CAS  Google Scholar 

  68. Dimitri, A., Burns, J. A., Broyde, S. & Scicchitano, D. A. Transcription elongation past O6-methylguanine by human RNA polymerase II and bacteriophage T7 RNA polymerase. Nucleic Acids Res. 36, 6459–6471 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Dosanjh, M. K., Loechler, E. L. & Singer, B. Evidence from in vitro replication that O6-methylguanine can adopt multiple conformations. Proc. Natl Acad. Sci. USA 90, 3983–3987 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Luch, A. Nature and nurture — lessons from chemical carcinogenesis. Nature Rev. Cancer 5, 113–125 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Choi, D. J., Roth, R. B., Liu, T., Geacintov, N. E. & Scicchitano, D. A. Incorrect base insertion and prematurely terminated transcripts during T7 RNA polymerase transcription elongation past benzo[a]pyrenediol epoxide-modified DNA. J. Mol. Biol. 264, 213–219 (1996).

    Article  CAS  PubMed  Google Scholar 

  72. Loeb, L. A. & Preston, B. D. Mutagenesis by apurinic/apyrimidinic sites. Annu. Rev. Genet. 20, 201–230 (1986).

    Article  CAS  PubMed  Google Scholar 

  73. Liu, J. & Doetsch, P. W. Template strand gap bypass is a general property of prokaryotic RNA polymerases: implications for elongation mechanisms. Biochemistry 35, 14999–15008 (1996).

    Article  CAS  PubMed  Google Scholar 

  74. Zhou, W., Reines, D. & Doetsch, P. W. T7 RNA polymerase bypass of large gaps on the template strand reveals a critical role of the nontemplate strand in elongation. Cell 82, 577–585 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Maynard, S., Schurman, S. H., Harboe, C., de Souza-Pinto, N. C. & Bohr, V. A. Base excision repair of oxidative DNA damage and association with cancer and aging. Carcinogenesis 30, 2–10 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Tudek, B. Base excision repair modulation as a risk factor for human cancers. Mol. Aspects Med. 28, 258–275 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Wilson, D. M. & Bohr, V. A. The mechanics of base excision repair, and its relationship to aging and disease. DNA Repair (Amst.) 6, 544–559 (2007).

    Article  CAS  Google Scholar 

  78. Negrini, S., Gorgoulis, V. G. & Halazonetis, T. D. Genomic instability — an evolving hallmark of cancer. Nature Rev. Mol. Cell. Biol. 11, 220–228 (2010).

    Article  CAS  Google Scholar 

  79. Sweasy, J. B., Lang, T. & DiMaio, D. Is base excision repair a tumor suppressor mechanism? Cell Cycle 5, 250–259 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Holmquist, G. P. Cell-selfish modes of evolution and mutations directed after transcriptional bypass. Mutat. Res. 510, 141–152 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Rodin, S. N., Rodin, A. S., Juhasz, A. & Holmquist, G. P. Cancerous hyper-mutagenesis in p53 genes is possibly associated with transcriptional bypass of DNA lesions. Mutat. Res. 510, 153–168 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Wang, Z., Gerstein, M. & Snyder, M. RNA-Seq: a revolutionary tool for transcriptomics. Nature Rev. Genet. 10, 57–63 (2009).

    Article  CAS  PubMed  Google Scholar 

  83. Derheimer, F. A. et al. RPA and ATR link transcriptional stress to p53. Proc. Natl Acad. Sci. USA 104, 12778–12783 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ljungman, M. & Zhang, F. Blockage of RNA polymerase as a possible trigger for UV light-induced apoptosis. Oncogene 13, 823–831 (1996).

    CAS  PubMed  Google Scholar 

  85. Yamaizumi, M. & Sugano, T. UV-induced nuclear accumulation of p53 is evoked through DNA damage of actively transcribed genes independent of the cell cycle. Oncogene 9, 2775–2784 (1994).

    CAS  PubMed  Google Scholar 

  86. Frosina, G. The current evidence for defective repair of oxidatively damaged DNA in Cockayne syndrome. Free Radic. Biol. Med. 43, 165–177 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Cooper, P. K., Nouspikel, T. & Clarkson, S. G. Retraction. Science 308, 1740 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Cozzarelli, N. R. Editorial expression of concern. Proc. Natl Acad. Sci. USA 100, 11816 (2003).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  89. Le Page, F. et al. Transcription-coupled repair of 8-oxoguanine: requirement for XPG, TFIIH and CSB and implications for Cockayne syndrome. Cell 123, 711 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Spivak, G. & Hanawalt, P. C. Host cell reactivation of plasmids containing oxidative DNA lesions is defective in Cockayne syndrome but normal in UV-sensitive syndrome fibroblasts. DNA Repair (Amst.) 5, 13–22 (2006).

    Article  CAS  Google Scholar 

  91. Pastoriza-Gallego, M., Armier, J. & Sarasin, A. Transcription through 8-oxoguanine in DNA repair-proficient and Csb−/Ogg1− DNA repair-deficient mouse embryonic fibroblasts is dependent upon promoter strength and sequence context. Mutagenesis 22, 343–351 (2007).

    Article  CAS  PubMed  Google Scholar 

  92. Larsen, E., Kwon, K., Coin, F., Egly, J. M. & Klungland, A. Transcription activities at 8-oxoG lesions in DNA. DNA Repair (Amst.) 3, 1457–1468 (2004).

    Article  CAS  Google Scholar 

  93. El-Agnaf, O. M. et al. Aggregates from mutant and wild-type alpha-synuclein proteins and NAC peptide induce apoptotic cell death in human neuroblastoma cells by formation of b-sheet and amyloid-like filaments. FEBS Lett. 440, 71–75 (1998).

    Article  CAS  PubMed  Google Scholar 

  94. van Leeuwen, F. W. et al. Frameshift mutants of b amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients. Science 279, 242–247 (1998).

    Article  CAS  PubMed  Google Scholar 

  95. Lovell, M. A., Gabbita, S. P. & Markesbery, W. R. Increased DNA oxidation and decreased levels of repair products in Alzheimer's disease ventricular CSF. J. Neurochem. 72, 771–776 (1999).

    Article  CAS  PubMed  Google Scholar 

  96. Xu, G., Herzig, M., Rotrekl, V. & Walter, C. A. Base excision repair, aging and health span. Mech. Ageing Dev. 129, 366–382 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Bridges, B. A. Starvation-associated mutation in Escherichia coli: a spontaneous lesion hypothesis for “directed” mutation. Mutat. Res. 307, 149–156 (1994).

    Article  CAS  PubMed  Google Scholar 

  98. Bridges, B. A. Mutation in resting cells: the role of endogenous DNA damage. Cancer Surv. 28, 155–167 (1996).

    CAS  PubMed  Google Scholar 

  99. Brégeon, D., Matic, I., Radman, M. & Taddei, F. Inefficient mismatch repair: genetic defects and down regulation. J. Genet. 78, 21–28 (1999).

    Article  Google Scholar 

  100. Vaisman, A. & Woodgate, R. Unique misinsertion specificity of poliota may decrease the mutagenic potential of deaminated cytosines. EMBO J. 20, 6520–6529 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kreutzer, D. A. & Essigmann, J. M. Oxidized, deaminated cytosines are a source of C → T transitions in vivo. Proc. Natl Acad. Sci. USA 95, 3578–3582 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Belousova, E. A. et al. DNA polymerases β and λ bypass thymine glycol in gapped DNA structures. Biochemistry 49, 4695–4704 (2010).

    Article  CAS  PubMed  Google Scholar 

  103. Clark, J. M. & Beardsley, G. P. Thymine glycol lesions terminate chain elongation by DNA polymerase I in vitro. Nucleic Acids Res. 14, 737–749 (1986).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Gu, F. et al. Peroxynitrite-induced reactions of synthetic oligo 2′-deoxynucleotides and DNA containing guanine: formation and stability of a 5-guanidino-4-nitroimidazole lesion. Biochemistry 41, 7508–7518 (2002).

    Article  CAS  PubMed  Google Scholar 

  105. Neeley, W. L. et al. DNA polymerase V allows bypass of toxic guanine oxidation products in vivo. J. Biol. Chem. 282, 12741–12748 (2007).

    Article  CAS  PubMed  Google Scholar 

  106. Shibutani, S., Takeshita, M. & Grollman, A. P. Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG. Nature 349, 431–434 (1991).

    Article  CAS  PubMed  Google Scholar 

  107. Yoon, J. H., Prakash, L. & Prakash, S. Highly error-free role of DNA polymerase η in the replicative bypass of UV-induced pyrimidine dimers in mouse and human cells. Proc. Natl Acad. Sci. USA 106, 18219–18224 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kuraoka, I. et al. Oxygen free radical damage to DNA translesion synthesis by human DNA polymerase η and resistance to exonuclease action at cyclopurine deoxynucleoside residues. J. Biol. Chem. 276, 49283–49288 (2001).

    Article  CAS  PubMed  Google Scholar 

  109. Vaisman, A., Masutani, C., Hanaoka, F. & Chaney, S. G. Efficient translesion replication past oxaliplatin and cisplatin GpG adducts by human DNA polymerase η. Biochemistry 39, 4575–4580 (2000).

    Article  CAS  PubMed  Google Scholar 

  110. Chary, P. & Lloyd, R. S. In vitro replication by prokaryotic and eukaryotic polymerases on DNA templates containing site-specific and stereospecific benzo[a]pyrene-7, 8-dihydrodiol-9, 10-epoxide adducts. Nucleic Acids Res. 23, 1398–1405 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Mah, M. C., Boldt, J., Culp, S. J., Maher, V. M. & McCormick, J. J. Replication of acetylaminofluorene-adducted plasmids in human cells: spectrum of base substitutions and evidence of excision repair. Proc. Natl Acad. Sci. USA 88, 10193–10197 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Gupta, P. K. et al. Mutagenesis by single site-specific arylamine-DNA adducts. Induction of mutations at multiple sites. J. Biol. Chem. 264, 20120–20130 (1989).

    Article  CAS  PubMed  Google Scholar 

  113. Shibutani, S., Takeshita, M. & Grollman, A. P. Translesional synthesis on DNA templates containing a single abasic site. A mechanistic study of the “A rule”. J. Biol. Chem. 272, 13916–13922 (1997).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank past and present members of the Doetsch laboratory for their helpful discussions and enthusiasm for the concept of transcriptional mutagenesis. D.B. is supported by Univeristé Paris-Sud 11 and Centre National de la Recherche Scientifique (CNRS). For transcriptional mutagenesis studies, P.W.D. is supported by the US National Institutes of Health grants R01-CA120288 and P30-CA138292.

Author information

Authors and Affiliations

  1. Damien Brégeon is at Université Paris Sud-11, Institut de Génétique et Microbiologie, CNRS UMR 8621, Bât 400, F-91405 Orsay Cedex, France.,

    Damien Brégeon

  2. Paul W. Doetsch is at Departments of Biochemistry and Radiation Oncology, Winship Cancer Institute, Emory University School of Medicine, 1510 Clifton Rd NE, Atlanta, Georgia 30322, USA.,

    Paul W. Doetsch

Authors
  1. Damien Brégeon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul W. Doetsch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul W. Doetsch.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

National Cancer Institute Drug Dictionary

Cisplatin

IARC TP53 Mutation Database

FURTHER INFORMATION

Damien Brégeon's homepage

Paul W. Doetsch's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brégeon, D., Doetsch, P. Transcriptional mutagenesis: causes and involvement in tumour development. Nat Rev Cancer 11, 218–227 (2011). https://doi.org/10.1038/nrc3006

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3006

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer