A FORMALISM FOR ANALYZING LARGE-SCALE CLUSTERING OF RADIATION-INDUCEDBREAKS ALONG CHROMOSOMES

Purpose: To model intrachromosomal clustering of DSB (DNA double stran d breaks) induced by ionizing radiation. That DSB are located non-rand omly along chromosomes after high LET irradiation, with clustering eve n at extremely large scales, has been confirmed by recent pulsed field gel electrophoresis data for size distributions of DNA fragments. We therefore extend the standard random-breakage model for DNA fragment-s ize distributions to a more general 'clustered-breakage' formalism, wh ich can take correlations of DSB locations along a chromosome into acc ount. Methods: The new formalism is based mainly on a one-track probab ility distribution, describing the DNA fragment-size pattern due to a single primary high-energy particle, a pattern determined by track str ucture and chromatin geometry. Multi-track fragment-size distributions are derived mathematically from the one-track distribution, so that d ose-response relations are obtained. Results: The clustered-breakage f ormalism is applicable to any chromosomal geometry and any radiation t rack structure. it facilitates extrapolations of high-dose data to the much lower doses of interest for most applications. When applied to r ecently published data for irradiation of mammalian cells with ions of LET approximate to 100 keV mu m(-1) it indicates a pattern of Mbp-sca le DSB clusters, each containing a number of DSB and corresponding to a very large-scale, multiply-damaged chromatin site. Although DSB are bunched, DSB clusters are scattered almost at random throughout the ge nome. Estimates of DSB yield are markedly increased by resolving such clusters into individual DSB. The dose-response relation for fragments of a given size becomes non-linear when clusters from different track s interlace or adjoin, as can occur for high doses and large sizes. Co nclusions: DSB clustering along chromosomes, which influences importan t radiobiological endpoints, is described quantitatively by the cluste red-breakage formalism.