Role of Membranes, Free Radicals, and Copper in Radiation-Induced Changes in Quaternary Structure of DNA: Some Clinical Implications
On challenge with 2 M NaCl, the nuclei of human lymphocytes yield an aggregate of DNA-protein material. The density of the material is less when isolated from irradiated cells than when isolated from nonirradiated cells. The density of this material [designated histone-free DNA (HF-DNA)] from irradiated cells returns to that from nonirradiated cells if the irradiated cells are allowed time at 37°C in nutrient conditions.
Lymphocytes from elderly donors and from patients with some connective tissue diseases were significantly less able to restore the density of HF-DNA after irradiation. In addition, lymphocyte HF-DNA from patients who have exhibited hypersensitivity to radiotherapy exhibits slower repair characteristics than does lymphocyte HF-DNA from the average normal subject. It may be possible from prospective studies to identify potentially sensitive patients, especially where radiotherapy regimens unavoidably include lymphocytic populations in the field of irradiation, and to modify such regimens accordingly.
The radiobiological properties of this HF-DNA from human lymphocytes suggest that radiation-induced alterations in the relatively weak cellular bonds responsible for the structure of chromatin are prime reasons for the consequent cellular malfunction. Where the proliferation of human lymphocytes, from which HF-DNA has been derived, has been measured by concanavalin A stimulation, oxygen enhancement ratios, relative biological effectiveness of densely ionizing radiation, and chemical modification have been of the same order as density changes in HF-DNA.
Also, we have found that the density of HF-DNA is heavily dependent on Cu (copper) content. This has led us to propose that cell killing or malfunction at the nuclear level caused by ionizing radiation is a result of the conversion of CuII → CuI and specific OH attack on DNA or proteins at a Cu site.
It is conceivable that these events interact and that the new molecular species produced predominate in the presence of oxygen. There will be a variability in sensitivity between cell types dependent on intrinsic chromatin levels of CuII and CuI and, of course, capacities to restore original configurations of macromolecular complexes.
KeywordsSystemic Lupus Erythematosus Connective Tissue Disease Human Lymphocyte Relative Biological Effectiveness Irradiate Cell
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