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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA037848-06
Application #
3175709
Study Section
Radiation Study Section (RAD)
Project Start
1984-08-15
Project End
1990-07-31
Budget Start
1989-08-01
Budget End
1990-07-31
Support Year
6
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Chicago
Department
Type
Organized Research Units
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Chen, W; Blazek, E R; Rosenberg, I (1995) The relaxation of supercoiled DNA molecules as a biophysical dosimeter for ionizing radiations: a feasibility study. Med Phys 22:1369-75
Peak, J G; Peak, M J (1995) Induction of slowly developing alkali-labile sites in human P3 cell DNA by UVA and blue- and green-light photons: action spectrum. Photochem Photobiol 61:484-7
Dudek, E J; Peak, J G; Roth, R M et al. (1993) Isolation of V79 fibroblast cell lines containing elevated metallothionein levels that have increased resistance to the cytotoxic effects of ultraviolet-A radiation. Photochem Photobiol 58:836-40
Blazek, E R; Alderfer, J L; Tabaczynski, W A et al. (1993) A 5-4 pyrimidine-pyrimidone photoproduct produced from mixtures of thymine and 4-thiouridine irradiated with 334 nm light. Photochem Photobiol 57:255-65
Blazek, E R; Peak, J G (1992) Filter elution assays for DNA damage: practical and mechanistic significance of the DNA in the filter support wash. Radiat Res 130:384-8
Churchill, M E; Peak, J G; Peak, M J (1991) Correlation between cell survival and DNA single-strand break repair proficiency in the Chinese hamster ovary cell lines AA8 and EM9 irradiated with 365-nm ultraviolet-A radiation. Photochem Photobiol 53:229-36
Peak, J G; Peak, M J (1991) Comparison of initial yields of DNA-to-protein crosslinks and single-strand breaks induced in cultured human cells by far- and near-ultraviolet light, blue light and X-rays. Mutat Res 246:187-91
Churchill, M E; Peak, J G; Peak, M J (1991) Repair of near-visible- and blue-light-induced DNA single-strand breaks by the CHO cell lines AA8 and EM9. Photochem Photobiol 54:639-44
Peak, J G; Pilas, B; Dudek, E J et al. (1991) DNA breaks caused by monochromatic 365 nm ultraviolet-A radiation or hydrogen peroxide and their repair in human epithelioid and xeroderma pigmentosum cells. Photochem Photobiol 54:197-203
Peak, M J; Peak, J G (1990) Hydroxyl radical quenching agents protect against DNA breakage caused by both 365-nm UVA and by gamma radiation. Photochem Photobiol 51:649-52

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