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. 1999 Dec;77(6):3218–3226. doi: 10.1016/S0006-3495(99)77152-3

Abasic sites in duplex DNA: molecular modeling of sequence-dependent effects on conformation.

L Ayadi 1, C Coulombeau 1, R Lavery 1
PMCID: PMC1300592  PMID: 10585943

Abstract

Molecular modeling calculations using JUnction Minimization of Nucleic Acids (JUMNA) have been used to study sequence effects on the conformation of abasic sites within duplex DNA. We have considered lesions leading to all possible unpaired bases (X), adenine, guanine, cytosine, or thymine contained within two distinct sequence contexts, CXC and GXG. Calculations were carried out on DNA 11-mers using extensive conformational search techniques to locate the most stable abasic conformations and using Poisson-Boltzmann corrected electrostatics to account for solvation effects. The results, which are in very good agreement with available experimental data, point to strong sequence effects on both the position of the unpaired base (intra or extrahelical) and on the overall curvature induced by the abasic lesion. For CXC, unpaired purines are found to lie within the helix, while unpaired pyrimidines are either extrahelical or in equilibrium between the intra and extrahelical forms. For GXG, all unpaired bases lead to intrahelical forms, but with marked, sequence-dependent differences in induced curvature.

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Selected References

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  1. Arnott S., Chandrasekaran R., Birdsall D. L., Leslie A. G., Ratliff R. L. Left-handed DNA helices. Nature. 1980 Feb 21;283(5749):743–745. doi: 10.1038/283743a0. [DOI] [PubMed] [Google Scholar]
  2. Barzilay G., Hickson I. D. Structure and function of apurinic/apyrimidinic endonucleases. Bioessays. 1995 Aug;17(8):713–719. doi: 10.1002/bies.950170808. [DOI] [PubMed] [Google Scholar]
  3. Boiteux S., Laval J. Coding properties of poly(deoxycytidylic acid) templates containing uracil or apyrimidinic sites: in vitro modulation of mutagenesis by deoxyribonucleic acid repair enzymes. Biochemistry. 1982 Dec 21;21(26):6746–6751. doi: 10.1021/bi00269a020. [DOI] [PubMed] [Google Scholar]
  4. Coppel Y., Berthet N., Coulombeau C., Coulombeau C., Garcia J., Lhomme J. Solution conformation of an abasic DNA undecamer duplex d(CGCACXCACGC) x d(GCGTGTGTGCG): the unpaired thymine stacks inside the helix. Biochemistry. 1997 Apr 22;36(16):4817–4830. doi: 10.1021/bi962677y. [DOI] [PubMed] [Google Scholar]
  5. Cuniasse P., Fazakerley G. V., Guschlbauer W., Kaplan B. E., Sowers L. C. The abasic site as a challenge to DNA polymerase. A nuclear magnetic resonance study of G, C and T opposite a model abasic site. J Mol Biol. 1990 May 20;213(2):303–314. doi: 10.1016/S0022-2836(05)80192-5. [DOI] [PubMed] [Google Scholar]
  6. Cuniasse P., Sowers L. C., Eritja R., Kaplan B., Goodman M. F., Cognet J. A., Le Bret M., Guschlbauer W., Fazakerley G. V. Abasic frameshift in DNA. Solution conformation determined by proton NMR and molecular mechanics calculations. Biochemistry. 1989 Mar 7;28(5):2018–2026. doi: 10.1021/bi00431a009. [DOI] [PubMed] [Google Scholar]
  7. Cuniasse P., Sowers L. C., Eritja R., Kaplan B., Goodman M. F., Cognet J. A., LeBret M., Guschlbauer W., Fazakerley G. V. An abasic site in DNA. Solution conformation determined by proton NMR and molecular mechanics calculations. Nucleic Acids Res. 1987 Oct 12;15(19):8003–8022. doi: 10.1093/nar/15.19.8003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Definitions and nomenclature of nucleic acid structure parameters. J Mol Biol. 1989 Feb 20;205(4):787–791. doi: 10.1016/0022-2836(89)90324-0. [DOI] [PubMed] [Google Scholar]
  9. Demple B., Harrison L. Repair of oxidative damage to DNA: enzymology and biology. Annu Rev Biochem. 1994;63:915–948. doi: 10.1146/annurev.bi.63.070194.004411. [DOI] [PubMed] [Google Scholar]
  10. Doetsch P. W. What's old is new: an alternative DNA excision repair pathway. Trends Biochem Sci. 1995 Oct;20(10):384–386. doi: 10.1016/s0968-0004(00)89084-2. [DOI] [PubMed] [Google Scholar]
  11. Gelfand C. A., Plum G. E., Grollman A. P., Johnson F., Breslauer K. J. Thermodynamic consequences of an abasic lesion in duplex DNA are strongly dependent on base sequence. Biochemistry. 1998 May 19;37(20):7321–7327. doi: 10.1021/bi9803372. [DOI] [PubMed] [Google Scholar]
  12. Gilson M. K., Honig B. Calculation of the total electrostatic energy of a macromolecular system: solvation energies, binding energies, and conformational analysis. Proteins. 1988;4(1):7–18. doi: 10.1002/prot.340040104. [DOI] [PubMed] [Google Scholar]
  13. Gorman M. A., Morera S., Rothwell D. G., de La Fortelle E., Mol C. D., Tainer J. A., Hickson I. D., Freemont P. S. The crystal structure of the human DNA repair endonuclease HAP1 suggests the recognition of extra-helical deoxyribose at DNA abasic sites. EMBO J. 1997 Nov 3;16(21):6548–6558. doi: 10.1093/emboj/16.21.6548. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Greger B., Kemper B. An apyrimidinic site kinks DNA and triggers incision by endonuclease VII of phage T4. Nucleic Acids Res. 1998 Oct 1;26(19):4432–4438. doi: 10.1093/nar/26.19.4432. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ide H., Shimizu H., Kimura Y., Sakamoto S., Makino K., Glackin M., Wallace S. S., Nakamuta H., Sasaki M., Sugimoto N. Influence of alpha-deoxyadenosine on the stability and structure of DNA. Thermodynamic and molecular mechanics studies. Biochemistry. 1995 May 30;34(21):6947–6955. doi: 10.1021/bi00021a006. [DOI] [PubMed] [Google Scholar]
  16. Joshua-Tor L., Rabinovich D., Hope H., Frolow F., Appella E., Sussman J. L. The three-dimensional structure of a DNA duplex containing looped-out bases. Nature. 1988 Jul 7;334(6177):82–84. doi: 10.1038/334082a0. [DOI] [PubMed] [Google Scholar]
  17. Jourdan M., Garcia J., Defrancq E., Kotera M., Lhomme J. 2'-deoxyribonolactone lesion in DNA: refined solution structure determined by nuclear magnetic resonance and molecular modeling. Biochemistry. 1999 Mar 30;38(13):3985–3995. doi: 10.1021/bi982743r. [DOI] [PubMed] [Google Scholar]
  18. Kalnik M. W., Chang C. N., Grollman A. P., Patel D. J. NMR studies of abasic sites in DNA duplexes: deoxyadenosine stacks into the helix opposite the cyclic analogue of 2-deoxyribose. Biochemistry. 1988 Feb 9;27(3):924–931. doi: 10.1021/bi00403a013. [DOI] [PubMed] [Google Scholar]
  19. Kalnik M. W., Chang C. N., Johnson F., Grollman A. P., Patel D. J. NMR studies of abasic sites in DNA duplexes: deoxyadenosine stacks into the helix opposite acyclic lesions. Biochemistry. 1989 Apr 18;28(8):3373–3383. doi: 10.1021/bi00434a037. [DOI] [PubMed] [Google Scholar]
  20. Lavery R., Sklenar H. Defining the structure of irregular nucleic acids: conventions and principles. J Biomol Struct Dyn. 1989 Feb;6(4):655–667. doi: 10.1080/07391102.1989.10507728. [DOI] [PubMed] [Google Scholar]
  21. Lavery R., Sklenar H. The definition of generalized helicoidal parameters and of axis curvature for irregular nucleic acids. J Biomol Struct Dyn. 1988 Aug;6(1):63–91. doi: 10.1080/07391102.1988.10506483. [DOI] [PubMed] [Google Scholar]
  22. Letellier R., Taillandier E., Bertrand J. R., Malvy C. Molecular modelling of 9-aminoellipticine interactions with abasic oligonucleotides. J Biomol Struct Dyn. 1991 Dec;9(3):579–597. doi: 10.1080/07391102.1991.10507938. [DOI] [PubMed] [Google Scholar]
  23. Lin Z., Hung K. N., Grollman A. P., de los Santos C. Solution structure of duplex DNA containing an extrahelical abasic site analog determined by NMR spectroscopy and molecular dynamics. Nucleic Acids Res. 1998 May 15;26(10):2385–2391. doi: 10.1093/nar/26.10.2385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lindahl T. Instability and decay of the primary structure of DNA. Nature. 1993 Apr 22;362(6422):709–715. doi: 10.1038/362709a0. [DOI] [PubMed] [Google Scholar]
  25. Lindahl T., Nyberg B. Rate of depurination of native deoxyribonucleic acid. Biochemistry. 1972 Sep 12;11(19):3610–3618. doi: 10.1021/bi00769a018. [DOI] [PubMed] [Google Scholar]
  26. Loeb L. A., Preston B. D. Mutagenesis by apurinic/apyrimidinic sites. Annu Rev Genet. 1986;20:201–230. doi: 10.1146/annurev.ge.20.120186.001221. [DOI] [PubMed] [Google Scholar]
  27. Miller M., Harrison R. W., Wlodawer A., Appella E., Sussman J. L. Crystal structure of 15-mer DNA duplex containing unpaired bases. Nature. 1988 Jul 7;334(6177):85–86. doi: 10.1038/334085a0. [DOI] [PubMed] [Google Scholar]
  28. Millican T. A., Mock G. A., Chauncey M. A., Patel T. P., Eaton M. A., Gunning J., Cutbush S. D., Neidle S., Mann J. Synthesis and biophysical studies of short oligodeoxynucleotides with novel modifications: a possible approach to the problem of mixed base oligodeoxynucleotide synthesis. Nucleic Acids Res. 1984 Oct 11;12(19):7435–7453. doi: 10.1093/nar/12.19.7435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Mol C. D., Kuo C. F., Thayer M. M., Cunningham R. P., Tainer J. A. Structure and function of the multifunctional DNA-repair enzyme exonuclease III. Nature. 1995 Mar 23;374(6520):381–386. doi: 10.1038/374381a0. [DOI] [PubMed] [Google Scholar]
  30. Morden K. M., Gunn B. M., Maskos K. NMR studies of a deoxyribodecanucleotide containing an extrahelical thymidine surrounded by an oligo(dA).oligo(dT) tract. Biochemistry. 1990 Sep 18;29(37):8835–8845. doi: 10.1021/bi00489a047. [DOI] [PubMed] [Google Scholar]
  31. Poncin M., Hartmann B., Lavery R. Conformational sub-states in B-DNA. J Mol Biol. 1992 Aug 5;226(3):775–794. doi: 10.1016/0022-2836(92)90632-t. [DOI] [PubMed] [Google Scholar]
  32. Sanghani S. R., Zakrzewska K., Harvey S. C., Lavery R. Molecular modelling of (A4T4NN)n and (T4A4NN)n: sequence elements responsible for curvature. Nucleic Acids Res. 1996 May 1;24(9):1632–1637. doi: 10.1093/nar/24.9.1632. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sharp K. A., Honig B. Electrostatic interactions in macromolecules: theory and applications. Annu Rev Biophys Biophys Chem. 1990;19:301–332. doi: 10.1146/annurev.bb.19.060190.001505. [DOI] [PubMed] [Google Scholar]
  34. Shida T., Noda M., Sekiguchi J. Cleavage of single- and double-stranded DNAs containing an abasic residue by Escherichia coli exonuclease III (AP endonuclease VI). Nucleic Acids Res. 1996 Nov 15;24(22):4572–4576. doi: 10.1093/nar/24.22.4572. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Takeshita M., Chang C. N., Johnson F., Will S., Grollman A. P. Oligodeoxynucleotides containing synthetic abasic sites. Model substrates for DNA polymerases and apurinic/apyrimidinic endonucleases. J Biol Chem. 1987 Jul 25;262(21):10171–10179. [PubMed] [Google Scholar]
  36. Wallace S. S. AP endonucleases and DNA glycosylases that recognize oxidative DNA damage. Environ Mol Mutagen. 1988;12(4):431–477. doi: 10.1002/em.2860120411. [DOI] [PubMed] [Google Scholar]
  37. Zacharias M., Sklenar H. Analysis of the stability of looped-out and stacked-in conformations of an adenine bulge in DNA using a continuum model for solvent and ions. Biophys J. 1997 Dec;73(6):2990–3003. doi: 10.1016/S0006-3495(97)78328-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Zacharias M., Sklenar H. Conformational analysis of single-base bulges in A-form DNA and RNA using a hierarchical approach and energetic evaluation with a continuum solvent model. J Mol Biol. 1999 Jun 4;289(2):261–275. doi: 10.1006/jmbi.1999.2760. [DOI] [PubMed] [Google Scholar]

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