A polymer, random walk model for the size-distribution of large DNA fragments after high linear energy transfer radiation.
DNA double-strand breaks (DSBs) produced by densely ionizing radiation are not located randomly in the genome: recent data indicate DSB clustering along chromosomes. Stochastic DSB clustering at large scales, from > 100 Mbp down to < 0.01 Mbp, is modeled using computer simulations and analytic equations. A random-walk, coarse-grained polymer model for chromatin is combined with a simple track structure model in Monte Carlo software called DNAbreak and is applied to data on alpha-particle irradiation of V-79 cells. The chromatin model neglects molecular details but systematically incorporates an increase in average spatial separation between two DNA loci as the number of base-pairs between the loci increases. Fragment-size distributions obtained using DNAbreak match data on large fragments about as well as distributions previously obtained with a less mechanistic approach. Dose-response relations, linear at small doses of high linear energy transfer (LET) radiation, are obtained. They are found to be non-linear when the dose becomes so large that there is a significant probability of overlapping or close juxtaposition, along one chromosome, for different DSB clusters from different tracks. The non-linearity is more evident for large fragments than for small. The DNAbreak results furnish an example of the RLC (randomly located clusters) analytic formalism, which generalizes the broken-stick fragment-size distribution of the random-breakage model that is often applied to low-LET data.
NASA ISC, Houston, TX 77058, USA. artemp@bem.tme.edu
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Ponomarev
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Brenner
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Hlatky
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RK
Sachs
D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000528:radiation effects*; D016000:Cluster Analysis; D004247:DNA / Q000528:radiation effects*; D004249:DNA Damage; D004307:Dose-Response Relationship, Radiation; D018499:Linear Energy Transfer; D015233:Models, Statistical; D009010:Monte Carlo Method; D012984:Software; D016615:Telomere / Q000528:radiation effects
D002843:Chromatin; D004247:DNA