Purpose : To investigate the role of kinetics in the processing of DNA doub
le strand breaks (DSB), and the formation of simple chromosome exchange abe
rrations following X-ray exposures to mammalian cells based on an enzymatic
approach.
Methods: Using computer simulations based on a biochemical approach, rate-e
quations that describe the processing of DSB through the formation of a DNA
-enzyme complex were formulated. A second model that allows for competition
between two processing pathways was also formulated. The formation of simp
le exchange aberrations was modelled as misrepair during the recombination
of single DSB with undamaged DNA. Non-linear coupled differential equations
corresponding to biochemical pathways were solved numerically by fitting t
o experimental data.
Results: When mediated by a DSB-repair enzyme complex, the processing of si
ngle DSB showed a complex behaviour that gives the appearance of fast and s
low components of rejoining. This is due to the time-delay caused by the ac
tion time of enzymes in biomolecular reactions. It is shown that the kineti
c- and dose-responses of simple chromosome exchange aberrations are well de
scribed by a recombination model of DSB interacting with undamaged DNA when
aberration formation increases with linear dose-dependence. Competition be
tween two or more recombination processes is shown to lead to the formation
of simple exchange aberrations with a dose-dependence similar to that of a
linear-quadratic model.
Conclusions : Using a minimal number of assumptions, the kinetics and dose-
response observed experimentally for DSB rejoining and the formation of sim
ple chromosome exchange aberrations are shown to be consistent with kinetic
models based on enzymatic reaction approaches. A non-linear dose-response
for simple exchange aberrations is possible in a model of recombination of
DNA containing a DSB with undamaged DNA when two or more pathways compete f
or DSB repair.