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Preferential cissyn thymine dimer bypass by DNA polymerase η occurs with biased fidelity


Human DNA polymerase η (Pol η) modulates susceptibility to skin cancer by promoting DNA synthesis past sunlight-induced cyclobutane pyrimidine dimers that escape nucleotide excision repair (NER)1,2. Here we have determined the efficiency and fidelity of dimer bypass. We show that Pol η copies thymine dimers and the flanking bases with higher processivity than it copies undamaged DNA, and then switches to less processive synthesis. This ability of Pol η to sense the dimer location as synthesis proceeds may facilitate polymerase switching before and after lesion bypass. Pol η bypasses a dimer with low fidelity and with higher error rates at the 3′ thymine than at the 5′ thymine. A similar bias is seen with Sulfolobus solfataricus DNA polymerase 4, which forms a Watson–Crick base pair at the 3′ thymine of a dimer but a Hoogsteen base pair at the 5′ thymine (ref. 3). Ultraviolet-induced mutagenesis is also higher at the 3′ base of dipyrimidine sequences4,5,6. Thus, in normal people and particularly in individuals with NER-defective xeroderma pigmentosum who accumulate dimers, errors made by Pol η during dimer bypass could contribute to mutagenesis and skin cancer.

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Figure 1: CPD bypass by Pol η.
Figure 2: CPD bypass by S. solfataricus Dpo4.
Figure 3: Error rates for undamaged thymine and TT dimer bypass.


  1. Masutani, C. et al. The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase η. Nature 399, 700–704 (1999)

    Article  ADS  CAS  Google Scholar 

  2. Johnson, R. E., Kondratick, C. M., Prakash, S. & Prakash, L. hRAD30 mutations in the variant form of xeroderma pigmentosum. Science 285, 263–265 (1999)

    Article  CAS  Google Scholar 

  3. Ling, H., Boudsocq, F., Plosky, B. S., Woodgate, R. & Yang, W. Replication of a cissyn thymine dimer at atomic resolution. Nature 424, 1083–1087 (2003)

    Article  ADS  CAS  Google Scholar 

  4. Armstrong, J. D. & Kunz, B. A. Site and strand specificity of UVB mutagenesis in the SUP4-o gene of yeast. Proc. Natl Acad. Sci USA 87, 9005–9009 (1990)

    Article  ADS  CAS  Google Scholar 

  5. Dumaz, N., Stary, A., Soussi, T., Daya-Grosjean, L. & Sarasin, A. Can we predict solar ultraviolet radiation as the causal event in human tumours by analyzing the mutation spectra of the p53 gene? Mutat. Res. 307, 375–386 (1994)

    Article  CAS  Google Scholar 

  6. Hsia, H. C., Lebkowski, J. S., Leong, P.-M., Calos, M. P. & Miller, J. H. Comparison of ultraviolet irradiation-induced mutagenesis of the lacI gene in Escherichia coli and in human 293 cells. J. Mol. Biol. 205, 103–113 (1989)

    Article  CAS  Google Scholar 

  7. Kokoska, R. J., McCulloch, S. D. & Kunkel, T. A. The efficiency and specificity of apurinic/apyrimidinic site bypass by human DNA polymerase η and Sulfolobus solfataricus Dpo4. J. Biol. Chem. 278, 50537–50545 (2003)

    Article  CAS  Google Scholar 

  8. Masutani, C., Kusumoto, R., Iwai, S. & Hanaoka, F. Mechanisms of accurate translesion synthesis by human DNA polymerase η. EMBO J. 19, 3100–3109 (2000)

    Article  CAS  Google Scholar 

  9. Park, H. et al. Crystal structure of a DNA decamer containing a cissyn thymine dimer. Proc. Natl Acad. Sci USA 99, 15965–15970 (2002)

    Article  ADS  CAS  Google Scholar 

  10. Washington, M. T., Prakash, L. & Prakash, S. Mechanism of nucleotide incorporation opposite a thymine–thymine dimer by yeast DNA polymerases η. Proc. Natl Acad. Sci. USA 100, 12093–12098 (2003)

    Article  ADS  CAS  Google Scholar 

  11. Boudsocq, F., Iwai, S., Hanaoka, F. & Woodgate, R. Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4): an archaeal DinB-like DNA polymerase with lesion-bypass properties akin to eukaryotic pol η. Nucleic Acids Res. 29, 4607–4616 (2001)

    Article  CAS  Google Scholar 

  12. Shcherbakova, P. V., Bebenek, K. & Kunkel, T. A. Functions of eukaryotic DNA polymerases. Sci. Aging Knowledge Environ. [online], 26 February 2003 〈;2003/8/ref3

  13. Trincao, J. et al. Structure of the catalytic core of S. cerevisiae DNA polymerase η: implications for translesion DNA synthesis. Mol. Cell 8, 417–426 (2001)

    Article  CAS  Google Scholar 

  14. Ling, H., Boudsocq, F., Woodgate, R. & Yang, W. Crystal structure of a Y-family DNA polymerase in action: a mechanism for error-prone and lesion-bypass replication. Cell 107, 91–102 (2001)

    Article  CAS  Google Scholar 

  15. Johnson, R. E., Washington, M. T., Prakash, S. & Prakash, L. Fidelity of human DNA polymerase η. J. Biol. Chem. 275, 7447–7450 (2000)

    Article  CAS  Google Scholar 

  16. Friedberg, E. C., Walker, G. C. & Siede, W. DNA Repair and Mutagenesis 544–555 (ASM, Washington DC, 1995)

    Google Scholar 

  17. Matsuda, T., Bebenek, K., Masutani, C., Hanaoka, F. & Kunkel, T. A. Low fidelity DNA synthesis by human DNA polymerase-η. Nature 404, 1011–1013 (2000)

    Article  ADS  CAS  Google Scholar 

  18. Matsuda, T. et al. Error rate and specificity of human and murine DNA polymerase η. J. Mol. Biol. 312, 335–346 (2001)

    Article  CAS  Google Scholar 

  19. Prakash, S. & Prakash, L. Translesion DNA synthesis in eukaryotes: a one- or two-polymerase affair. Genes Dev. 16, 1872–1883 (2002)

    Article  CAS  Google Scholar 

  20. Bresson, A. & Fuchs, R. P. Lesion bypass in yeast cells: Pol η participates in a multi-DNA polymerase process. EMBO J. 21, 3881–3887 (2002)

    Article  CAS  Google Scholar 

  21. Marini, F., Kim, N., Schuffert, A. & Wood, R. D. POLN, a nuclear PolA family DNA polymerase homologous to the DNA cross-link sensitivity protein Mus308. J. Biol. Chem. 278, 32014–32019 (2003)

    Article  CAS  Google Scholar 

  22. O'Day, C. L., Burgers, P. M. J. & Taylor, J. PCNA-induced DNA synthesis past cissyn and transsyn-I thymine dimers by calf thymus DNA polymerase δ in vitro. Nucleic Acids Res. 20, 5403–5406 (1992)

    Article  CAS  Google Scholar 

  23. Tissier, A. et al. Misinsertion and bypass of thymine–thymine dimers by human DNA polymerase ι. EMBO J. 19, 5259–5266 (2000)

    Article  CAS  Google Scholar 

  24. Nelson, J. R., Lawrence, C. W. & Hinkle, D. C. Thymine–thymine dimer bypass by yeast DNA polymerase ζ. Science 272, 1646–1649 (1996)

    Article  ADS  CAS  Google Scholar 

  25. Zhang, Y. et al. Lesion bypass activities of human DNA polymerase µ. J. Biol. Chem. 277, 44582–44587 (2002)

    Article  CAS  Google Scholar 

  26. Ohashi, E. et al. Error-prone bypass of certain DNA lesions by the human DNA polymerase κ. Genes Dev. 14, 1589–1594 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang, H. & Siede, W. UV-induced T → C transition at a TT photoproduct site is dependent on Saccharomyces cerevisiae polymerase η in vivo. Nucleic Acids Res. 30, 1262–1267 (2002)

    Article  CAS  Google Scholar 

  28. Murata, T., Iwai, S. & Ohtsuka, E. Synthesis and characterization of a substrate for T4 endonuclease V containing a phosphorodithioate linkage at the thymine dimer site. Nucleic Acids Res. 18, 7279–7286 (1990)

    Article  CAS  Google Scholar 

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We thank Y. Pavlov and K. Bebenek for discussions and comments on the manuscript.

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Correspondence to Thomas A. Kunkel.

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McCulloch, S., Kokoska, R., Masutani, C. et al. Preferential cissyn thymine dimer bypass by DNA polymerase η occurs with biased fidelity. Nature 428, 97–100 (2004).

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