This grant application requests continued support for CA46838 (Analysis of Radiation Damage in DNA). A noteworthy achievement during the previous three years of support for CA46838 was the discovery by NMR spectroscopy of free radical-induced tandem damages in DNA oligomers. Four sequence dependent tandem base lesions were identified, two of which are produced when oxygen is available; the other two tandem lesions are produced in the absence of oxygen. In either the presence or absence of oxygen tandem base damage is a principal form of free radical-induced damage in DNA oligomers. Continued funding of CA46838 would permit a thorough search for other tandem lesions. The prevalence of tandem lesions in DNA and the factors that influence production of tandem lesions, such as sequence and conformation, will be investigated. Another objective is to include tandem lesions in 32P-postlabeling assay that will detect several DNA lesions representative of free-radical induced damage. The assay will utilize dimer carriers, and approach to 32P-postlabeling developed in this laboratory. It is suggested that this assay may serve as a convenient measure of genomic instability. Proton NMR spectroscopy, especially NOSEY and COSY will be employed in a 2D study of the effect of various lesions, especially tandem lesions, on molecular conformation. Also, templates containing identified lesions will be constructed for use in an in vitro assay that will evaluate the propensity of specific free radical-induced lesions to cause mutations.
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