Journal of the American Chemical Society
Article
(6) Cadet, J.; Douki, T.; Ravanat, J.-L. Free Radical Biol. Med. 2010,
49, 9.
(7) Qi, Y.; Spong, M. C.; Nam, K.; Banerjee, A.; Jiralerspong, S.;
Karplus, M.; Verdine, G. L. Nature 2009, 462, 762.
(8) Coste, F.; Ober, M.; Carell, T.; Boiteux, S.; Zelwer, C.; Castaing,
B. J. Biol. Chem. 2004, 279, 44074.
internal H-bond, known to be quite strong in similar systems. It
seems that this H-bond allows the dGf lesion to adopt a quasi-
heterocyclic structure, with the result that the dGf structure can
function as a standard nucleobase (Figure 5), which explains
(9) Leipold, M. D.; Workman, H.; Muller, J. G.; Burrows, C. J.;
David, S. S. Biochemistry 2003, 42, 11373.
(10) Scharer, O. D. Angew. Chem., Int. Ed. 2003, 42, 2946.
(11) Serre, L.; De, J. K. P.; Boiteux, S.; Zelwer, C.; Castaing, B.
EMBO J. 2002, 21, 2854.
(12) Fromme, J. C.; Verdine, G. L. Nat. Struct. Biol. 2002, 9, 544.
(13) Burrows, C. J.; Muller, J. G. Chem. Rev. 1998, 98, 1109.
(14) Cadet, J.; Douki, T.; Ravanat, J.-L. Acc. Chem. Res. 2008, 41,
1075.
(15) Dizdaroglu, M.; Kirkali, G.; Jaruga, P. Free Radical Biol. Med.
2008, 45, 1610.
(16) Ober, M.; Linne, U.; Gierlich, J.; Carell, T. Angew. Chem., Int.
Ed. 2003, 42, 4947.
(17) Tudek, B. J. Biochem. Mol. Biol. 2003, 36, 12.
(18) Neeley, W. L.; Essigmann, J. M. Chem. Res. Toxicol. 2006, 19,
491.
(19) Raoul, S.; Berger, M.; Buchko, G. W.; Joshi, P. C.; Morin, B.;
Weinfeld, M.; Cadet, J. J. Chem. Soc., Perkin Trans. 2 1996, 371.
(20) Cadet, J.; Berger, M.; Buchko, G. W.; Joshi, P. C.; Raoul, S.;
Ravanat, J.-L. J. Am. Chem. Soc. 1994, 116, 7403.
(21) Luo, W.; Muller, J. G.; Burrows, C. J. Org. Letters 2001, 3, 2801.
(22) Tudek, B.; Winczura, A.; Janik, J.; Siomek, A.; Foksinski, M.;
Olinski, R. Am. J. Transl. Res. 2010, 2, 254.
(23) Sedelnikova, O. A.; Redon, C. E.; Dickey, J. S.; Nakamura, A. J.;
Georgakilas, A. G.; Bonner, W. M. Mutat. Res., Rev. Mutat. Res. 2010,
704, 152.
Figure 5. Possible base pairs formed between dGf and dG, dA, and
dC.
the efficient bypass. In this cyclic structure, the dGf compound
can, however, exist in different tautomeric forms, which could
be responsible for the flexible coding properties as depicted in
Figure 5.
CONCLUSION
■
In summary we report the discovery of a new intermediate
along the oxidative dG degradation pathway. The new dGf-
lesion constitutes a significant barrier to replication in vitro, but
depending on the polymerase, substantial bypass is observed as
well. The flexible base pairing properties of the compound
direct polymerases to pair it in a severely error-prone manner,
thus rendering it a highly mutagenic lesion. This property is
explained by us with a rigid, cyclic structure of the lesion held
together by an intramolecular hydrogen bond and by the
existence of different tautomeric states.
(24) Radak, Z.; Boldogh, I. Free Radical Biol. Med. 2010, 49, 587.
(25) Hsu, G. W.; Ober, M.; Carell, T.; Beese, L. S. Nature 2004, 431,
217.
(26) Delaney, M. O.; Wiederholt, C. J.; Greenberg, M. M. Angew.
Chem., Int. Ed. 2002, 41, 771.
(27) Ober, M.; Mueller, H.; Pieck, C.; Gierlich, J.; Carell, T. J. Am.
Chem. Soc. 2005, 127, 18143.
(28) Kino, K.; Sugiyama, H. Chem. Biol. 2001, 8, 369.
(29) Kino, K.; Saito, I.; Sugiyama, H. J. Am. Chem. Soc. 1998, 120,
7373.
(30) Gasparutto, D.; Ravanat, J. L.; Gerot, O.; Cadet, J. J. Am. Chem.
Soc. 1998, 120, 10283.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, supplementary figures, and detailed
mass spectra. This material is available free of charge via the
■
S
(31) Matsuda, A.; Shinozaki, M.; Suzuki, M.; Watanabe, K.; Miyasaka,
T. Synthesis 1986, 1986, 385.
(32) Wei, G.; Loktionova, N. A.; Pegg, A. E.; Moschel, R. C. J. Med.
Chem. 2005, 48, 256.
AUTHOR INFORMATION
Corresponding Author
■
́ ́
(33) Ronaghi, M.; Uhlen, M.; Nyren, P. Science 1998, 281, 363.
(34) Munzel, M.; Lischke, U.; Stathis, D.; Pfaffeneder, T.; Gnerlich,
F. A.; Deiml, C. A.; Koch, S. C.; Karaghiosoff, K.; Carell, T. Chemistry
2011, 17, 13782−13788.
Notes
The authors declare no competing financial interest.
(35) Neeley, W. L.; Delaney, J. C.; Henderson, P. T.; Essigmann, J.
M. J. Biol. Chem. 2004, 279, 43568.
(36) Prakash, S.; Johnson, R. E.; Prakash, L. Annu. Rev. Biochem.
ACKNOWLEDGMENTS
■
This work was supported by the Deutsche Forschungsgemein-
schaft (SFB749 and CA275/8-4) and the Volkswagen
Foundation. We thank Toni Pfaffeneder for his help with the
HPLC-MS/MS experiments and Dr. Markus Muller for critical
reading of the manuscript.
2005, 74, 317.
(37) Hubscher, U.; Maga, G.; Spadari, S. Annu. Rev. Biochem. 2002,
71, 133.
(38) Bernard S, S. DNA Repair 2002, 1, 125.
(39) Sagher, D.; Strauss, B. Biochemistry 1983, 22, 4518.
(40) Kunkel, T. A.; Schaaper, R. M.; Loeb, L. A. Biochemistry 1983,
22, 2378.
(41) Boiteux, S.; Laval, J. Biochemistry 1982, 21, 6746.
(42) Duarte, V.; Gasparutto, D.; Jaquinod, M.; Cadet, J. Nucleic Acids
Res. 2000, 28, 1555.
̈
REFERENCES
■
(1) Steenken, S.; Jovanovic, S. V. J. Am. Chem. Soc. 1997, 119, 617.
(2) Cadet, J.; Douki, T.; Gasparutto, D.; Ravanat, J.-L. Mutat. Res.,
Fundam. Mol. Mech. Mutagen. 2003, 531, 5.
(43) Kino, K.; Sugiyama, H. Mutat. Res., Fundam. Mol. Mech.
(3) Cadet, J.; Courdavault, S.; Ravanat, J.-L.; Douki, T. Pure Appl.
Mutagen. 2005, 571, 33.
Chem. 2005, 77, 947.
(44) Kino, K.; Sugasawa, K.; Mizuno, T.; Bando, T.; Sugiyama, H.;
Akita, M.; Miyazawa, H.; Hanaoka, F. ChemBioChem 2009, 10, 2613.
(4) Gimisis, T.; Cismas, C. Eur. J. Org. Chem. 2006, 1351.
(5) Pratviel, G.; Meunier, B. Chem.Eur. J. 2006, 12, 6018.
4929
dx.doi.org/10.1021/ja211435d | J. Am. Chem. Soc. 2012, 134, 4925−4930