Review: Proximity effects in the production of chromosome aberrations by ionizing radiation

Abstract

After ionizing radiation has induced double-strand DNA breaks dsb, misrejoining produces chromosome aberrations. Aberration yields are influenced by 'proximity' effects, i.e. by the dependence of misrejoining probabilities on initial dsb separations. We survey proximity effects, emphasizing implications for chromosome aberration-formation mechanisms, for chromatin geometry, and for dose-response relations. Evidence for proximity effects comes from observed biases for centric rings and against three-way interchanges, relative to dicentrics or translocations. Other evidence comes from the way aberration yields depend on radiation dose and quality, tightly bunched ionizations being relatively effective. We conclude: 1 that misrejoining probabilities decrease as the distance between dsb at the time of their formation increases, and almost all misrejoining occurs among dsb initially separated by 1 3 of a cell nucleus diameter; 2 that chromosomes occupy irregular territories during the G0 G1 phase of the cell cycle, having dimensions also roughly 1 3 of a cell nucleus diameter; 3 that proximity effects have the potential to probe how much different chromosomes intertwine or move relative to each other; and 4 that incorporation of proximity effects into the classic random breakage-and-reunion model allows quantitative interrelation of yields for many different aberration types and of data obtained with various FISH painting methods or whole-genome scoring.