title: DNA Distortion Caused by Uracil-Containing Intrastrand Cross-Links.
abstract: Four uracil-containing intrastrand cross-links have been detected in human cells upon UV irradiation of 5-bromouracil-containing DNA, namely 5'-G[8-5]U-3', 5'-U[5-8]G-3', 5'-A[8-5]U-3', and 5'-A[2-5]U-3'. These lesions feature unique composition and connectivity compared with other intrastrand cross-links reported in the literature. For the first time, structural information obtained using molecular dynamics (MD) simulations reveal that all four lesions distort the DNA helix, which can involve an extrahelical location of the cross-link, changes in the helical interactions of the complementary nucleotides, or disruption of hydrogen bonding in the flanking base pairs up to two positions from the cross-linked site; however, the degree of distortion varies between the cross-links, being affected by the sequence, nucleobase-nucleobase connectivity, and the purine involved. Most importantly, the relative distortion of the damaged DNA provides the first structural explanation for the observed abundances of the four uracil-containing cross-links. Furthermore, the highly distorted conformations suggest that these lesions will likely have severe implications for DNA replication and repair processes in cells.
authors.affiliation: Department of Chemistry and Biochemistry, University of Lethbridge , 4401 University Drive West, Lethbridge, Alberta T1K 3M4, Canada.
authors.forename: Cassandra D M
authors.initials: CD
authors.lastname: Churchill
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg , Box 462, Göteborg 405 30, Sweden.
authors.forename: Leif A
authors.initials: LA
authors.lastname: Eriksson
authors.affiliation: Department of Chemistry and Biochemistry, University of Lethbridge , 4401 University Drive West, Lethbridge, Alberta T1K 3M4, Canada.
authors.forename: Stacey D
authors.initials: SD
authors.lastname: Wetmore
mesh_terms: D001976:Bromouracil / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D018736:DNA Adducts / Q000737:chemistry*; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation / Q000187:drug effects / Q000528:radiation effects; D014466:Ultraviolet Rays; D014498:Uracil / Q000737:chemistry*
chemical_list: D003432:Cross-Linking Reagents; D018736:DNA Adducts; D001976:Bromouracil; D014498:Uracil