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Mathematical modeling of repair systems in living organisms

Mathematical modeling of repair systems in living organisms. MOHAMED ABDELMOEZ AHMED SOLYMAN SCHOLARSHIP STUDENT IN NATIONAL CENTER OF RADIATION RESEARCH & TECHNOLOGY- EGYPT ATOMIC ENERGY AUTHORITY.

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Mathematical modeling of repair systems in living organisms

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  1. Mathematical modeling of repair systems in living organisms

  2. MOHAMED ABDELMOEZ AHMED SOLYMANSCHOLARSHIP STUDENT IN NATIONAL CENTER OF RADIATION RESEARCH & TECHNOLOGY- EGYPT ATOMIC ENERGY AUTHORITY

  3. JOINT INSTITUTEFOR NUCLEAR RESEARCH Laboratory of Radiation Biologyunder supervisorDr. Oleg Belov

  4. Mathematical modeling of repair of DNA single strand breaks in Escherichia coli bacterial cells

  5. DNA damage due to environmental factors and normal metabolic processes inside the cell, occurs at a rate of 1,000 to 1,000,000 molecular lesions per cell per day of the human genome's

  6. Agents that Damage DNA • Certain wavelengths of radiation • ionizing radiation such as gamma rays , X-rays and heavy ions • ultraviolet radiation, especially the UV-C rays (~220-290 nm) that are absorbed strongly by DNA but also the longer-wavelength UV-B that penetrates the ozone shield. • Highly-reactive oxygen radicals produced during normal cellular respiration as well as by other biochemical pathways. • Chemicals in the environment • many hydrocarbons, including some found in cigarette smoke • some plant and microbial products, e.g. the aflatoxins produced in moldy peanuts • Chemicals used in chemotherapy, especially chemotherapy of cancers

  7. The effect of different type of radiation • UV lightcauses crosslinking between adjacent cytosine and thymine bases creating pyrimidine dimers. This is called direct DNA damage. • Ionizing radiationsuch as that created by radioactive decay or in cosmic rays and particle accelerators causes DNA damages of various types. There two type of effect of ionizing radiation: direct and indirect.

  8. Types of DNA Damage • Breaks in the DNA backbone • can be limited to one of the two strands (a single-stranded break, SSB) • on both strands (a double-stranded break (DSB). • Base damage • Sugar damage • Mismatches of the normal bases because of a failure of proofreading during DNA replication. • Common example: incorporation of the pyrimidine U (normally found only in RNA) instead of T. • Crosslinks Covalent linkages can be formed between bases • on the same DNA strand ("intrastrand") or • on the opposite strand ("interstrand").

  9. What’s the DNA Repair? • DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome

  10. Types of single strand breaks • 5'OH –terminus • 5'PO4 –terminus • 3' Free end group • 3' OH –terminus in ds DNA excluded • 3' OH –terminus in single strand site • 3'PO4 –terminus • 3'OH and 5'PO4 not divided by gaps

  11. DNA Single-Strand Breaks (SSBs) Repair • Breaks in a single strand of the DNA molecule are repaired by three types of mechanisms in Escherichia coli bacterial cells • Type I • Type II • Type III

  12. Type I Repair Mechanism • ultrafast repair, which mends single-strand breaks within1 min at 0⁰C • Nicks can be repaired by a DNA ligase if all that has happened is that a phosphodiester bond has been broken, without damage to the 5′-phosphate and 3′-hydroxyl groups of the nucleotides either side of the nick. This is often the case with nicks resulting from the effects of ionizing radiation. (DNA ligase is the same enzyme used to bond DNA strands together without DNA damage)

  13. Type I Repair Mechanism

  14. Type II Repair Mechanism • The DNA polymerase I (which have 3'-5' exonuclease activity) binds to single strand break to produce 3'OH group then start to produce new nucleotides • DNA ligase enzyme joining of the newly synthesized segment to the original strain • Repair of 5'OH , 3'PO4 and 3'OH in single stranded sites

  15. Type II Repair Mechanism

  16. Type III Repair Mechanism • DNA exonuclease III attack single strand break • The enzyme produce 3'OH termini suitable as primers for DNA polymerase I • The DNA polymerase I use 3'OH group as primer • DNA polymerase I starts to synthesize a new strand while displacing the DNA segment • The final step of the repair process is joining of the newly synthesized segment to the original strand by DNA ligase • Repair of 5'OH ,3'PO4, and 3‘ free group

  17. Type III Repair Mechanism

  18. STEPS TO MAKE MATHEMATICAL MODEL FOR REPAIR SYSTEM

  19. On the basis of experimental facts, determine the key processes making the main contribution to the functioning of the chosen DNA repair system.

  20. Convert this mechanism into chemical equations • DNA repair by type III • [3'PO4]+[Exo III] k1k-1 [3'PO4][Exo III] k2 [3'OH DNA]+[Exo III] • [3'OH]+[Pol I] k3k-3 [3'OH][Pol I] k4 [ULDNA]+[Pol I] • [ULDNA]+[DNA ligase] k5k-5 [ULDNA][DNA ligase] k6 [RDNA] +[DNA ligase]

  21. Find the numerical values of the parameters of the chosen DNA repair system Numerical values of the model parameters for type III

  22. Entire Simulation Input cv ( v=1,…,M) initi . Of Xi (i=1,…,N) Set t=0 & n=0 Generate random numbers r1 and r2 Calculate a1= hvcv ( v=1,…,M) a0 = av Generate random numbers r1 and r2 Take • Update t = t + t • Update X = [X1, X2, …XC] • Update n= n + 1 Construct a mathematical model of the chosen DNA repair system using the deterministic and stochastic approaches. Gillespie,1976

  23. Obtain and analyze solutions of the proposed model.

  24. RESULTS Type I Repair DNA Ligase Complex between un legated DNA and Ligase Repaired DNA

  25. RESULTS Type II Repair Repaired DNA Complex between break DNA and polymerase Complex between un legated DNA and Ligase DNA Ligase DNA polymerase I

  26. RESULTS Type III Repair DNA exonuclease III DNA polymerase I DNA Ligase

  27. RESULTS Type III Repair Complex between break DNA and exonuclease iii Repaired DNA Complex between un legated DNA and Ligase Complex between break DNA and polymerase

  28. Comparison between DNA ligase kineticks in different type of repair Type I Repair Type II Repair Type III Repair

  29. Comparison between DNA polymerase I kineticks in different type of repair Type III Repair Type II Repair

  30. SUMMARY • the mathematical model of repair of single strand DNA breaks was developed • the concentrations of key enzymes and DNA states was calculated at use of two different mathematical approaches

  31. FUTURE TASKS • we plan to use this simulation results for development of mathematical model of mutagenesis induced by ionizing radiation (accelerator heavy ions) • We plan to apply this model to other organisms (lactobacillus sp)

  32. Acknowledgements Firstly and forever, Thanks to ALLAH, who give me everything in my life, and I supplicate Allah to make my life in a perfect way. I wish to express my appreciation to Dr. Oleg Belov for constant encouragement and offering of facilities. I express my deepest gratitude and appreciation for sponsoring this work, tremendous effort, unfailing support, maximum accuracy and for his generous guidance advice

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