GENETIC/ CYTOGENETIC INSTABILITY OF IONIZING RADIATION

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Health concerns related to radiation exposure center on carcinogenesis and mutagenesis following doses that are typically too low to produce a measurable biological response. Quantitative, biologically relevant data is needed for low dose risk estimates, but this will ultimately require extrapolation guided by a knowledge of underlying mechanisms. There is mounting evidence that the appropriate mechanisms to study relate to the ability of ionizing radiations to destabilize the mammalian genome. Most such data relates to the delayed appearance of microscopically visible changes to chromosomes, or submicroscopic mutations following radiation exposure. Based on preliminary data presented, a working model has been constructed to explain chromosomal instability in terms of unstable junctions that can form at the interface of breakpoints involved in chromosome translocations and inversions. This basic concept allows for various predictions regarding the instability process that are represented by the five specific aims contained in the current proposal. These include the notions: 1) that chromosomal instability leads to the production of "non-reciprocally complex" exchanges that involve several chromosomes as part of the same rearrangement; 2) that inversions are the most frequent destabilizing event; 3) and that instability should be common feature of irradiated cells. Potential further implications of the model are: 4) that unstable rearrangements may ultimately lead to the acquisition of mutations at loci that are distantly removed from the breakpoints themselves; 5) and that translocations and inversions may inactivate genes via transcriptional silencing.