A unique characteristic of ionizing radiation and radiomimetic anticancer drugs is the induction of clustered damage: two or more DNA lesions (oxidized bases, abasic sites, or strand breaks) occurring in the same or different strands of the DNA molecule within a single turn of the helix. In spite of arising at a lower frequency than single lesions, clustered DNA damage represents an exotic challenge to the repair systems present in the cells and, in some cases, these lesions may escape detection and/or processing. To understand the structural properties of clustered DNA lesions we have prepared two oligodeoxynucleotide duplexes containing adjacent tetrahydrofuran residues (abasic site analogues), positioned one in each strand of the duplex in a 5' or 3' orientation, and determined their solution structure by NMR spectroscopy and molecular dynamics simulations. The NMR data indicate that both duplex structures are right-handed helices of high similarity outside the clustered damage site. The thermal stability of the duplexes is severely reduced by the presence of the abasic residues, especially in a 5' orientation where the melting temperature is 5 degrees C lower. The structures show remarkable differences at the lesion site where the extrahelical location of the tetrahydrofuran residues in the (AP)(2)-5'-staggered duplex contrasts with their smooth alignment along the sugar-phosphate backbone in the (AP)(2)-3'-staggered duplex.
NMR characterization of clustered bistrand abasic site lesions: effect of orientation on their solution structure.,Lin Z, de los Santos C J Mol Biol. 2001 Apr 27;308(2):341-52. PMID:11327771[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
↑ Lin Z, de los Santos C. NMR characterization of clustered bistrand abasic site lesions: effect of orientation on their solution structure. J Mol Biol. 2001 Apr 27;308(2):341-52. PMID:11327771 doi:10.1006/jmbi.2001.4587
