1. Nermeen Kamel Abe El Moniem Laboratory of Radiation Biology, JINR Supervised by Dr. Oleg Belov Modeling of DNA damages induction under ionizing radiation of various qualities

2. Output (Results) output Input1 Yield of DNA damages Input2 *Reaction Rates k1,…, kn * Initial Concentrations of proteins x o,y o,z o Why is it Important to Calculate the Yield of DNA Damages? Model of SSB repair Model of DSB repair Model of SOS system … Calculation of concentration change Calculation of mutation frequency …

3. Damages at some specific locations can lead to either cell death, or mutation or carcinogenesis. DNA Damage

4.  Models of radiation damage in DNA can give at least a qualitative insight as to the yields of such damages and their dependence on radiation quality.  The approach presented here comes from a knowledge of  Structure of DNA  Radiation Track Structure Calculation of DNA Damage

5.  There are four different types of nucleotides (monomer units) found in DNA, differing only in the nitrogenous base. The four nucleotides are A adenine G guanine C cytosine T thymine nucleotides. DNA Structure

6.  Track Structure is microscopic distribution of energy  Geometrical pattern of energy deposition around the trajectory of an incident particle. Track Structure

7. Energy can be deposited directly on the DNA molecule, creating ionized and excited states of the various molecules (sugar, bases, phosphates, etc.). These physical processes can also lead to DNA damage and are generally known as the direct effects of radiation Direct Effect of Radiation : Interaction of Ionizing Radiation With DNA

8. It has been demonstrated experimentally that the products of water due to radiation interaction can indirectly cause biochemical changes in a DNA molecule and this process is called the indirect affect of radiation damage Interaction of Ionizing Radiation With DNA Indirect Effect of Radiation :

9.  This model is based on the assumption that the distribution of damage to DNA follows the distribution of ionizing events within the molecule and its surroundings.  The damage due to direct effect is due to energy deposition directly in a DNA molecule.  The damage due to the indirect effect is supposed to be caused by *OH radicals produced in the water sheath around the DNA molecule containing bound water.  base ionization is equally probable to the ionization of the sugar phosphate backbone because electron densities of both are nearly the Assumptions of the Model

10. We need to calculate Calculations the Calculation is given by: The calculation of DNA damage is based on probability y i (j) that a cluster of j ionizations will result in a damage of the i th type (where i th type stands for type of break).

11. x the cluster overlaps the DNA We need to calculate area of sphere without this part. V(x) - volume of a given distance x of the center of cluster from DNA where cluster represented by a sphere of parameter equal to cluster parameter p The calculation of probability of having m ionizations out of the DNA and j-m within it if the cluster overlaps the DNA.

12. G(m) is the yield of OH* radicals per one ionization when m ionizations of given cluster is in water sheath around DNA. ρDNA is the probability that 'OH radical escaping scavenging will react with DNA Probability that m ionizations will result in k OH* radicals reacting with DNA.

13. Probability that j-m ionizations within DNA and k OH* radicals reacting with DNA (both have origin in the same cluster) will result in the ith type of damage.

14.  Now let us consider n ionizations in DNA molecule.  s 1 = s 2 = 0. 25 are the probabilities for one ionization in DNA to cause damage to the sugar phosphate backbone on the first (s 1 ) or on the second (s 2 ) strand.  b 1 = b 2 = 0. 25 are the respective probabilities for one ionization in DNA to cause base damage.  ρBSB=0.67 is the probability that damaged sugar will result in ssb. ρSD = 1 - ρSSB,  ρBSB = 0.1 is the probability that damaged base cause ssb and ρBD = 1- ρBSB.  S OH1 =S OH2 =0.1 is the probabilities for one OH radical to cause damage to the sugar-phosphate moiety on the first S OH1 or on the second (S OH2 ) strand. Variables

15. Results The calculations were performed for the following types of DNA damages:

16. Results Multiple strand break on one strand SSB + damaged opposite strand Single strand break Double strand break Cluster order j Damage probability 1 y ( j )

17. Conclusion An algorithm for calculation of the yield of different types of DNA damages was realized in Wolfram Mathematica package. The probability of DNA damages of various types was calculated in dependence on order of the cluster formed after the ionization in DNA.

18. This work is released under the joint project between laboratory of Radiation Biology and Cairo University. This work will be continued. Let N i be the yield of damages of the i th type per unit of deposited energy, then Where h(j) is the cluster distributions. For every type of radiation the probability that the cluster is isolated (i.e. there are no neighbor clusters within the distance of cluster parameter. N i is the value which we need to calculate next. Future task

19. Thank You for Your Attention