title: Formation mechanism and structure of a guanine-uracil DNA intrastrand cross-link.
abstract: The formation and structure of the 5'-G[8-5]U-3' intrastrand cross-link are studied using density functional theory and molecular dynamics simulations due to the potential role of this lesion in the activity of 5-halouracils in antitumor therapies. Upon UV irradiation of 5-halouracil-containing DNA, a guanine radical cation reacts with the uracil radical to form the cross-link, which involves phosphorescence or an intersystem crossing and a rate-determining step of bond formation. Following ionizing radiation, guanine and the uracil radical react, with a rate-limiting step involving hydrogen atom removal. Although cross-link formation from UV radiation is favored, comparison of calculated reaction thermokinetics with that for related experimentally observed purine-pyrimidine cross-links suggests this lesion is also likely to form from ionizing radiation. For the first time, the structure of 5'-G[8-5]U-3' within DNA is identified by molecular dynamics simulations. Furthermore, three conformations of cross-linked DNA are revealed, which differ in the configuration of the complementary bases. Distortions, such as unwinding, are localized to the cross-linked dinucleotide and complementary nucleotides, with minimal changes to the flanking bases. Global changes to the helix, such as bending and groove alterations, parallel cisplatin-induced distortions, which indicate 5'-G[8-5]U-3', may contribute to the cytotoxicity of halouracils in tumor cell DNA using similar mechanisms.
authors: Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive, Lethbridge, Alberta, Canada T1K 3M4.
authors: Cassandra D M
authors: CD
authors: Churchill
authors: Leif A
authors: LA
authors: Eriksson
authors: Stacey D
authors: SD
authors: Wetmore
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D006147:Guanine / Q000737:chemistry*; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D013816:Thermodynamics; D014466:Ultraviolet Rays; D014498:Uracil / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D014498:Uracil; D006147:Guanine; D004247:DNA