In higher eukaryotic cells, chromosomal aberrations are principally involved in all of the important biological effects of ionizing radiations, including cell reproductive death that is central to cancer therapy by radiation, and oncogenesis that is the principal hazard to the human population from low level ionizing radiation exposure. The goals of this project are to gain a better understanding of the mechanisms of aberration formation; to identify and characterize factors influencing types and frequencies of aberrations produced by radiation; and to explore and develop new approaches to the quantitative measurement of genetic effects of low level radiation exposure. Specifically our aims focus on studies of the nature of lesions that lead to aberration formation including an investigation of interphase chromosome breakage as expressed in prematurely condensed chromosomes (PCCs) as well as mitotic chromosomes. Comparisons would be made following treatment with agents other than ionizing radiation that also produce DNA double strand breaks. Further specific studies would be carried out to determine whether interphase chromosome breakage occurs preferentially in euchromatin or heterochromatin and whether metaphase aberrations from U.V. and x-rays occur predominantly in one or the other in Microtus agrestus cells with giant heterochromatic sex chromosomes. Studies on the inhibition of rejoining or increased expression of x-ray induced PCC breaks using anisotonic salt, ara-A, and caffeine treatments would also be undertaken with emphasis on the relationship of the effects observed to PLD and SLD """"""""repair"""""""". In addition, studies would be undertaken on the complementation in hybrid cells of a defect in cells from patients with Ataxia-Telangiectasia; first, to see whether the defect resulting in chromatid aberration production from G1 x-irradiation can be corrected by complementation in hybrids, and second to determine the chromosomal location of a human gene that corrects the defect leading to hypersensitivity in an x-ray sensitive mutant of CHO cells. Lastly, we would attempt to measure x-ray induced chromosomal abnormalities with higher resolution and greater sensitivity than has previously been possible, using EM preparations of synaptonemal complexes of early pachytene mouse spermatocytes. The goals and aims of this project are important for the scientific underpinning of cancer radiotherapy and for a fuller appreciation of genetic and oncogenic hazards of low level ionizing radiation exposure.
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