We propose to determine the three-dimensional structural consequences of chemical modification of DNA. Specifically, a number of chemicals including carcinogens will be reacted with DNA, usually oligonucleotides. These will be crystallized and the three-dimensional structure of the modified DNA will be determined. These experiments are designed to test the influence of carcinogen and chemical modification in altering DNA conformations. The three-dimensional structure determinations will be carried out by crystallizing fragments of synthetic DNA containing 6 to 20 base pairs that have been modified usually by the action of chemicals or carcinogens or in which the DNA is altered. A variety of changes is known to influence the conformation of DNA. These include change associated with depurination or loss of a base, altered conformations associated with mismatches between bases or with the insertion of extra bases. Likewise, the structure of DNA will be studied when it is modified by a number of reagents, including methylating reagents, oxidized states of bases, or through the formation of adducts as, for example, with benzo(a)pyrene, aflatoxin, or psoralin. These fragments will be crystallized and their three-dimensional conformation determined in order to understand the relation between DNA conformation and chemical modification. Knowlegde of the altered DNA conformation may lead to further understanding of mutational or carcinogenic mechanisms. Experiments will also be carried out comparing the manner in which these reagents attack left-handed Z-DNA compared to right-handed A or B-DNA. Since their conformations are different, they may show alternative routes of chemical modification. A search will also be carried out for novel DNA conformations associated with special sequences, such as homopurine homopyrimidine.
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