A new model for how O6-methylguanine-DNA methyltransferase binds DNA
Robin A. Vora
Section of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, New York
Search for more papers by this authorAnthony E. Pegg
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, Pennsylvania
Search for more papers by this authorCorresponding Author
Steven E. Ealick
Section of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, New York
Cornell University, 209 Biotechnology Building, Ithaca, NY 14850===Search for more papers by this authorRobin A. Vora
Section of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, New York
Search for more papers by this authorAnthony E. Pegg
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, Pennsylvania
Search for more papers by this authorCorresponding Author
Steven E. Ealick
Section of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, New York
Cornell University, 209 Biotechnology Building, Ithaca, NY 14850===Search for more papers by this authorAbstract
Human methyltransferase (hAT) catalyzes the transfer of an alkyl group from the 6-position of guanine to an active site Cys residue. The physiological role of hAT is the repair of alkylated guanine residues in DNA. However, the repair of methylated or chloroethylated guanine bases negates the effects of certain chemotherapeutic agents. A model of how hAT binds DNA might be useful in the design of compounds that could inactivate hAT. We have used computer modeling studies to generate such a model. The model utilizes a helix-loop-wing DNA binding motif found in Mu transposase. The model incorporates a flipped out guanine base in order to bring the methylated oxygen atom close to the active site Cys residue. The model is consistent with a variety of chemical and biochemical data. Proteins 32:3–6, 1998. © 1998 Wiley-Liss, Inc.
REFERENCES
- 1 Lindahl, T., Sedgwick, B., Sekiguchi, M., Nakabeppu Y. Regulation and expression of the adaptive response to alkylating agents. Annu. Rev. Biochem. 57: 133–157, 1988.
- 2 Samson, L. The suicidal DNA repair methyltransferases of microbes. Mol. Microbiol. 6: 825–831, 1992.
- 3 Pegg, A.E., Dolan, M.E., Moschel, R.C. Structure, function and inhibition of O6-alkylguanine-DNA alkyltransferase. Prog. Nucleic Acid Res. Mol. Biol. 51: 167–223, 1995.
- 4 Goodtzova, K., Kanugula, S., Edara, S. et al. Repair of O6-benzylguanine by the Escherichia coli Ada and Ogt and the human O6-alkylguanine-DNA alkyltransferase. J. Biol. Chem. 272: 8332–8339, 1997.
- 5 Saffhill, R., Margison, G.P., O'Connor, P.J. Mechanisms of carcinogenesis induced by alkylating agents. BBA 823: 111–146, 1985.
- 6 Singer, B., Essigmann, J.M. Site-specific mutagenesis retrospective and prospective. Carcinogenesis 12: 949–956, 1991.
- 7 Pegg, A.E., Mammalian O6-alkylguanine DNA alkyltransferase regulation and importance in response to alkylating carcinogenic and therapeutic agents. Cancer Res. 50: 6119–6129, 1990.
- 8 Bishop, R.E., Moschel, R.C. Positional effects on the structure and stability of abbreviated h-ras DNA-sequences containing O6 methylguanine residues at codon 12. Chem. Res. Toxicol. 4: 647–657, 1991.
- 9 Moore, M.H., Gulbis, J.M., Dodson, E.J, Demple, B., Moody, P.C.E. Crystal structure of a suicidal DNA repair protein: The Ada O6-methylguanine-DNA methyltransferase from E. Coli. EMBO J. 13: 1495–1501, 1994.
- 10 Moody, P.C.E., Moore, M.E. Crystal structure of E. coli O6-methylguanine-DNA methyltransferase. In: “ Novel Approaches in Anticancer Drug Design Molecular Modeling—New Treatment Strategies, Vol. 49.” W.J. Zeller, M. D'Incalci, D.R. Newell (eds.). Basel: Karger, 1995: 16–24.
- 11 Rost, B., Sander, C. Jury returns on structural prediction. Nature 360: 540, 1992.
- 12 Wibley, J.E.A., McKie, J.H., Embrey, K. et al. A homology model of the three-dimensional structure of human of O6-alkylguanine-DNA alkyltransferase based on the C-terminal domain of the Ada protein from Escherichia coli. Anti-Cancer Drug Des. 10: 75–95, 1995.
- 13 Pegg, A.E., Dolan, M.E., Moschel, R.C. Structure, function, and inhibition of O6- alkylguanine-DNA alkyltransferase. Prog. Nucleic Acid Res. Mol. Biol. 51: 167–223, 1995.
- 14 Demple, B. In: “ Protein Methylation.” W.K. Pailk, K. Kim (eds.). Boca Raton, FL: CRC Press, 1990.
- 15 Roberts, R. On base flipping. Cell 82: 9–12, 1995.
- 16 Murzin, A.G., Brenner, S.E., Hubbard, T., Chothia, C. Scop: A structural classification of proteins database for the investigation of sequences and structures. J. Mol. Biol. 247: 536–540, 1995.
- 17 Clubb, R.T., Omichinski, J.G., Savilahti, H. et al. A novel class of winged helix-turn-helix protein: The DNA-binding domain of Mu transposase. Structure 2: 1041–1048, 1994.
- 18 Kanugula, S., Goodtzova, K., Edara, S., Pegg, A.E. Alteration of arginine-128 to alanine abolishes the ability of human O6-alkylguanine-DNA alkyltransferase to repair methylated DNA but has no effect on its reaction with O6-benzylguanine. Biochemistry 34: 7113–7119, 1995.
- 19 Goodtzova, K., Kanugula, S., Edara, S., Pegg, A.E. The role of tyrosine 114 in O6-alkylguanine-DNA alkyltransferase activity. Proc. Am. Assoc. Cancer Res. 37: A2484, 1996.
- 20 Verdine, G.L. The flip side of DNA methylation. Cell 28: 197–200, 1994.
- 21 Demple, B. DNA repair flips out. Curr. Biol. 5: 719–721, 1995.
- 22 Cheng, X. DNA modification by methyltransferases. Curr. Opin. Struct. Biol. 5: 4–10, 1995.
- 23 Cheng, X., Blumenthal, R. Finding a basis for flipping bases. Structure 4: 639–645, 1996.
- 24 Klimasauskas, S., Kumar, S., Roberts, R., Cheng, X. HhaI methyltransferase flips its target base out of the DNA helix. Cell 76: 357–369, 1994.
- 25 Cal, S., Connolly, B.A. DNA distortion and base flipping by the Eco RV DNA methyltransferase. J. Biol. Chem. 272: 490–496, 1997.
- 26 Park, H., Kim, S., Sancar, A., Deisenhofer, J. Crystal structure of DNA photolyase from Escherichia coli. Science 268: 1866–1872, 1995.
- 27 Vassylyev, D.G., Kashiwagi, T., Mikami, Y. et al. Atomic model of a pyrimidine dimer exchange excision repair enzyme complexed with a DNA substrate: Structural basis for damaged DNA recognition. Cell 83: 773–782, 1995.
- 28 Labahn J., Schärer O.D., Long A. et al. Structural basis for the excision repair of alkylation-damaged DNA. Cell 86: 321–329, 1996.
- 29 Yamagata, Y., Kato, M., Odawara, K., Tokuno, Y., Nakashima, Y., Matsushima, N., Yasamura, K. Three-dimensional structure of a DNA repair enzyme, 3-methyladenine DNA glycosylase II, from Escherichia coli. Cell 86: 311–319, 1996.
- 30 Thayer, M.M., Ahern, H., Xing, D., Cunningham, R.P., Tainer, J.A. Novel DNA binding motifs in the DNA repair enzyme endonuclease III crystal structure. EMBO J. 16: 4108–4120, 1995.
- 31 Slupphaug, G., Moi, C., Kavli, B., Arvai, A., Krokan, H., Tainer, J. A nucleotide-flipping mechanism from the structure of human uracil-DNA glycosylase bound to DNA. Nature 384: 87–92, 1996.
- 32 Takahashi, M., Sakumi, K., Sekiguchi, M. Interaction of Ada protein with DNA examined by fluorescence anisotropy of the protein. Biochemistry 29: 3431–3436, 1990.
- 33 Cahn, C.Z.W., Ciardelli, T., Eastman, A., Bresnick, E. Kinetic and DNA-binding properties of recombinant human O6-methylguanine-DNA methyltransferase. Arch. Biochem. Biophys. 300: 193–200, 1993.
- 34 Patel, D.J., Shapiro, L., Kozlowski, S.A., Gaffney, B.L., Jones, R.A. Structural studies of the O6meG.C interaction in the d(C-G-C-A-A-T-T-C-O6meG-C-G) duplex. Biochemistry 25: 1027–1036, 1986.
- 35 Altschul, S.F., Gish, W., Miller, W., Myers, E., Lipman D. Basic local alignment search tool. J. Mol. Biol 215: 403–410, 1990.
Citing Literature
