Solar ultraviolet (UV) radiation is a proven toxicant, mutagen, and carcinogen; little is known however about the underlying molecular and chemical processes that cause these effects. One complex mechanism through which solar radiation, especially its longer wavelength components, damages DNA is the photosensitization reactions of photodynamic action. These particular reaction pathways operate via a variety of endogenous nonDNA sensitizer molecules, which become electronically excited by the nearultraviolet photons. These excited molecules, in turn, convert groundstate molecular oxygen into a range of reactive oxygen species that may react with DNA. Our research is now focused upon the identification of specific chemical changes in DNA caused by mutagenic and carcinogenic photosensitizations produced in cells by solar UV. We propose to examine the effects of certain photosensitizations upon nucleic acid bases, nucleotides, and DNA. These reactions can produce new, so far unidentified, photoproducts, especially of thymine. We propose to use DNA sequencing methodology to explore further sitespecific damages that are imposed by different photosensitization reactions (for instance, thymine is a preferred site of DNA damage caused by one sensitization reaction that we have studied, 334 nm UVA plus 4thiouridine). We also propose to use the same cloned DNA in a genetic transformation assay, to correlate chemical damage with biological damage and to obtain insights into possible repair pathways of specific lesions. For these efforts, we propose to combine the expertise in reactive oxygen species of N. I. Krinsky, and the analytical chemistry expertise and powerful analytical tools available through D. A. Haugen and V. C. Stamoudis with the photobiological and biophysical expertise of M. J. Peak and J. G. Peak. These insights may provide information relevant to our understanding of mechanisms underlying carcinogenesis, since solar UV radiations are the main etiological factor in the induciton of more than 70% of all human cancers.
Showing the most recent 10 out of 27 publications
