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Nucleic Acids Research Advance Access published online on November 19, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm622
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© 2007
The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Structural Biology

DNA oligonucleotides with A, T, G or C opposite an abasic site: structure and dynamics

Jingyang Chen1, François-Yves Dupradeau2, David A. Case2, Christopher J. Turner3 and JoAnne Stubbe1,4,*

1Department of Chemistry Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, 2Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, 3Francis Bitter Magnet Laboratory and 4Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA

*To whom correspondence should be addressed. Tel: +1 617 253 1814; Fax: +1 617 258 7247; Email: stubbe{at}mit.edu

Received June 7, 2007. Revised July 24, 2007. Accepted July 30, 2007.

Abasic sites are common DNA lesions resulting from spontaneous depurination and excision of damaged nucleobases by DNA repair enzymes. However, the influence of the local sequence context on the structure of the abasic site and ultimately, its recognition and repair, remains elusive. In the present study, duplex DNAs with three different bases (G, C or T) opposite an abasic site have been synthesized in the same sequence context (5'-CCA AAG6 XA8C CGG G-3', where X denotes the abasic site) and characterized by 2D NMR spectroscopy. Studies on a duplex DNA with an A opposite the abasic site in the same sequence has recently been reported [Chen,J., Dupradeau,F.-Y., Case,D.A., Turner,C.J. and Stubbe,J. (2007) Nuclear magnetic resonance structural studies and molecular modeling of duplex DNA containing normal and 4'-oxidized abasic sites. Biochemistry, 46, 3096–3107]. Molecular modeling based on NMR-derived distance and dihedral angle restraints and molecular dynamics calculations have been applied to determine structural models and conformational flexibility of each duplex. The results indicate that all four duplexes adopt an overall B-form conformation with each unpaired base stacked between adjacent bases intrahelically. The conformation around the abasic site is more perturbed when the base opposite to the lesion is a pyrimidine (C or T) than a purine (G or A). In both the former cases, the neighboring base pairs (G6-C21 and A8-T19) are closer to each other than those in B-form DNA. Molecular dynamics simulations reveal that transient H-bond interactions between the unpaired pyrimidine (C20 or T20) and the base 3' to the abasic site play an important role in perturbing the local conformation. These results provide structural insight into the dynamics of abasic sites that are intrinsically modulated by the bases opposite the abasic site.

Present address: Jingyang Chen, Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge St. Boston, MA 02114, USA.

Francois-Yves Dupradeau, DMAG, EA 3901, Faculté de Pharmacie, Université de Picardie Jules Verne, 1-3, rue des Louvels, 80037 Amiens Cedex 1, France.


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