Durante, M.

Friedrich, T.

Scholz, M.

Scholz, U.

Taucher-Scholz, G.

Tommasino, F.

GSI Repository

Application of a LEM based DNA DSB kinetic rejoining model to the analysisof dose dependence after photon irradiation∗F. Tommasino1, T. Friedrich1, U. Scholz1, 2, G. Taucher-Scholz1, M. Scholz1, and M. Durante1, 21GSI, Darmstadt, Germany; 2Institut fu¨r Festko¨rperphysik, Technische Universita¨t, Darmstadt, GermanyA DNA Double-Strand Break (DSB) kinetic rejoiningmodel has been recently presented [1], which is based onthe approach currently adopted in the Local Effect Model(LEM) for the description of radiation induced biologicaleffects [2]. Shortly, the photon dose response data and anamorphous track structure model are combined together tocalculate the initial pattern of DSB induced in the target(i. e. the cell nucleus). The chromatin contained insidethe nucleus is considered to be organized in so-called Gi-ant Loops, each one involving about 2 Mbp of genome [3].The presence of such high-order chromatin structures al-lows defining two different classes of DSB, namely iso-lated (iDSB) and clustered ones (cDSB). An iDSB is de-fined as a single lesion inside a loop, while a cDSB is char-acterized by the simultaneous presence of more than oneDSB. cDSB are expected to be more difficult for the cell torepair compared to iDSB, since they may result in the lossof the structural integrity of the chromatin loop, and possi-bly in the migration of DNA fragments from the DSB site.In order to describe the kinetics of DSB rejoining over time,the hypothesis is made, that iDSB are rejoined by the fastcomponent while cDSB are processed by the slow compo-nent of rejoining which are often observed in the experi-ments. Thus, LEM calculations of induced DSB patternsare combined with a biphasic exponential decay functionhaving a fast (τfast) and a slow (τslow) half-life, as de-scribed by the following equation:U(t) = Ffast · e−ln(2)τfastt+ Fslow · e−ln(2)τslowt (1)where Ffast and Fslow correspond to the fraction of ini-tial induced iDSB and cDSB, respectively. For a given dataset involving a single cell line and different radiation qual-ities, Eq. 1 is used to simultaneously fit the experimentalrejoining data. The initial fractions of iDSB and cDSB arefixed input parameters and characterize a specific dose andradiation quality, while the two half-life times are definedas global fit parameters. Further details can be found else-where [1,2].The described model has been already applied to a largedata set, where experiments performed using both low andhigh LET were included, obtaining an overall good agree-ment. The focus is now on the use of the model for theanalysis of a specific biological end point. Specifically, wewant to test the model ability to describe the delayed DSBrejoining observed after increasing doses of photon radia-tion [4]. In this case, the Poisson distribution is adopted for∗This work was supported by a DFG-funded Graduiertenkolleg (GRK1657). The work is part of HGS-HIRe.the calculation of initially induced DSB patterns. An exam-ple is shown in Fig. 1, where the effects of 20 and 200 Gyare compared. Both the experiments and the model clearlyshow a slowed-down rejoining at 200 Gy compared to thelower dose. Importantly, in the context of our model, thisis only due to an increased fraction of induced cDSB, sincethe two half-lives are defined as global fit parameters andtherefore are identical for all the considered doses. How-ever, in contrast to what shown by Cucinotta et al [4], otherworks have been published where a dose dependence wasnot observed [5,6]. Thus, more data are needed to furthersupport the results presented here.Figure 1: experimental data (symbols) and model predic-tions (lines) for the DSB rejoining over time after photonirradiation with 20 and 200 Gy. Experimental data weremeasured with filter elution techniques and are taken fromCucinotta et al [4].A successful analysis of the end point presented here wouldfurther confirm the validity of the model. At the same time,it would be supportive for the relevance of the proposedDSB classes, and more in general of DSB clustering at themicrometer level, for the description of radiation inducedbiological effects not only at high but also at low LET.References[1] Tommasino et al., Radiat Res, 180 (2013), pp. 524-38.[2] Friedrich et al., Int. J. Radiat. Biol., 88 (2012) pp. 103-7.[3] Yokota et al., J. Cell Biol., 130 (1995) pp. 1239-49.[4] Cucinotta et al., Int J Radiat Biol, 76 (2000), pp. 1463-74.[5] Lo¨brich et al., PNAS, 92 (1995), pp. 12050-4.[6] Ku¨hne et al., Cancer Res, 64 (2004), pp. 500-8.BIOPHYSICS-28 GSI SCIENTIFIC REPORT 2013230 doi:10.15120/GR-2014-1-BIOPHYSICS-28

Application of a LEM based DNA DSB kinetic rejoining model to the analysis of dose dependence after photon irradiation

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Application of a LEM based DNA DSB kinetic rejoining model to the analysis of dose dependence after photon irradiation

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