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Several antitumour drugs react with DNA to form interstrand cross-links, causing chromosomal alterations like DNA strand breakage and hyper-recombination on the DNA helix, necessitating repair of damage on both strands of the DNA. Two basic processes by which interstrand cross-link lesions are repaired, an error-free process and an error-prone process, rely on proteins in the nucleotide incision repair, homologous recombination and translesion DNA synthesis pathways.

Results show that the cross-link N(sup)4C-Ethyl-N(sup)4C interstrand in the undecamer deoxyoligonucleotide imitates the BCNU-induced G-C cross-link and the C-C cross-link, rendering this DNA duplex recognizable by different DNA repair mechanisms.

This articles describes the synthesis of N(sup)4C--ethyl--N(sup)4C interstrand cross-linked DNA duplexes employing N(sup)4C--ethyl--N(sup)4C phosphoramidite reagent. The ligated oligomers containing staggered cross-links exhibit differences in structure and stability with -GC- staggered cross-links disrupt hydrogen bonding and affecting helix stability by perturbing adjacent base pairs.

DNA duplexes with N4C-ethyl-N4C interstrand cross-links were synthesized.

A study characterizes the repair, structure, and flexibility of DNA that contains N4C-ethyl-N4C interstand DNA cross-link in two different orientations. A combination of (super 1)H nuclear magnetic resonance (NMR), restrained molecular dynamics simulations, and atomic force microscopy (AFM) was used to examine the structure and flexibility of DNA containing these cross-links.

Previous research has shown that intramolecular nucleic acid triplexes are useful models for studying the stability and structure of triple-stranded DNA as well as the relationships between various ligands and triple-strande Hoogsten binding domain and its relationship to the Watson-Crick domains in the molecule. DNA. The stability of intramolecular DNA triplexes can be attributed to the

We have developed a new method for determining the DNA-binding specificity of proteins. In DIP-chip (DNA immunoprecipitation with microarray detection), protein·DNA complexes are isolated from an in vitro mixture of purified protein and naked genomic DNA. Whole-genome DNA microarrays are used to identify the protein-bound DNA fragments, and the sequence of the identified fragments is used to derive binding-site descriptions. Using objective criteria for assessing the accuracy of DNA-binding motifs, and using yeast Leu3p as a model, we demonstrate that motifs determined by DIP-chip are as effective at predicting the location of bound proteins in vivo as are motifs determined by conventional low-throughput in vitro methods. [ABSTRACT FROM AUTHOR]

Examines the synthesis and characterization of duplexes with interstrand cross-links of different orientations. Formation of thermal transition temperatures; Stabilization of circular dichroism spectrum and molecular models; Migration of ligated oligomers by polyacrylamide gel.

Describes the synthesis and characterization of DNA duplexes containing an N[sup 4]C-ethyl-N[sup 4]C interstrand cross-link. Synthesis of duplexes with a defined interstrand cross-link; Incorporation of the duplexes into longer pieces of DNA; DNA repair; Bifunctional alkylating agents.

The solution structure of an interstrand cross-linked self-complementary oligodeoxynucleotide containing directly opposed alkylated N(4)C-ethyl-N(4)C cytosine bases was determined by molecular dynamics calculations guided by NMR-derived restraints. The undecamer d(CGAAACTTTCG)(2), where C represents directly opposed alkylated N(4)C-ethyl-N(4)C cytosine bases, serves as model for the cytotoxic cross-links formed by bifunctional alkylating agents used in cancer therapy. The structure of the duplex shows the cross-link protruding into the major groove. An increase in the diameter of the DNA at the pseudoplatform formed by the cross-linked residues creates an A-DNA characteristic hole in the central portion of the DNA. This results in a centrally underwound base step and a number of subsequent overwinding steps leading to an overall axis bend toward the major groove. The structure shows narrowing of both minor and major grooves in the proximity of the cross-link. The perturbation leads to preferential intrastrand base stacking, disruption of adjacent canonical (A.T) base pairing, and buckling of base pairs, the extent of which diminishes with progression away from the lesion site. Overall, the distortion induced by the cross-link spreads over three base pairs on the 5'- and 3'-sides of the cross-link.