Modelling the effect of incorporated halogenated pyrimidine on radiation-induced DNA strand breaks.
OBJECTIVE
To estimate the enhancement of DNA strand breaks induced by low linear energy transfer (LET) radiation in the presence of halogenated pyrimidines and to examine complexity and clustering properties of damage that could provide a correlation between DNA damage and lethality.


METHODS
Monte Carlo track structure methods were used to model and estimate the induction of strand breakage by X-ray photons with and without the incorporated Br/I deoxyuridine in cell-mimetic conditions. The increase of DNA strand break induction was modelled by taking into account the direct energy deposition and the reactions of radicals. The yield and spectrum of strand breaks were calculated at various degrees of Br/IdU incorporation. The excess strand breaks due to Br/IdU incorporation was assumed to be induced by highly reactive uracilyl radicals. Four mechanisms were considered for the production of uracilyl radicals classified into three groups, by hydrated electrons, by direct energy deposition, and by both hydrated electrons and direct energy depositions. In total, nine different models were considered to test the excess strand breaks by incorporated Br/IdU assuming different pathways.


RESULTS
Model calculations show the following: the yield of strand breaks is enhanced by both the e(aq)(-) reaction and the direct energy deposition on base moiety; there is a significant contribution to the enhancement of yield of strand breaks due to energy transfer about four bases along the DNA to Br/IdU and DNA strand break complexity increases with degree of Br/IdU incorporation. Enhancement ratios of 1.8 and 2.5 for 40% Br/IdU substitution were obtained for single- and double-strand breaks, respectively.


CONCLUSIONS
The increase in the yield of strand breaks due to Br/IdU incorporation could be explained by the mechanism of uracilyl radical production by e(aq)(-) and direct energy deposition. The importance of energy transfer along the DNA is demonstrated. It is shown that the incorporation of Br/IdU causes a spectral shift towards a greater complexity of clustered DNA damage.
Watanabe
R
R
Radiation Risk Analysis Laboratory, Department of Health Physics, Japan Atomic Energy Research Institute, Tokai, Ibaraki 319-1195, Japan.
Nikjoo
H
H
D001483:Base Sequence; D001973:Bromodeoxyuridine / Q000737:chemistry / Q000528:radiation effects*; D019457:Chromosome Breakage; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry / Q000528:radiation effects*; D004249:DNA Damage; D004307:Dose-Response Relationship, Radiation; D005609:Free Radicals / Q000737:chemistry; D007065:Idoxuridine / Q000737:chemistry / Q000528:radiation effects*; D018499:Linear Energy Transfer; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009010:Monte Carlo Method; D011836:Radiation Tolerance; D014498:Uracil / Q000737:chemistry / Q000528:radiation effects; D014867:Water / Q000737:chemistry
D005609:Free Radicals; D014867:Water; D014498:Uracil; D004247:DNA; D001973:Bromodeoxyuridine; D007065:Idoxuridine