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

Agents that Damage DNACertain 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

The effect of different type of radiationUV light causes crosslinking between adjacent

cytosine and thymine bases creating pyrimidine dimers. This is called direct DNA damage.

Ionizing radiation such 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.

Types of DNA DamageBreaks 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 damageSugar 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").

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

Types of single strand breaks5'OH –terminus5'PO4 –terminus3' Free end group3' 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

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 cellsType IType IIType III

ultrafast repair, which mends single-strand breaks within1 min at 0 C⁰

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)

Type I Repair Mechanism

Type I Repair Mechanism

1. 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

2. 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

Type II Repair Mechanism

Type II Repair Mechanism

1. DNA exonuclease III attack single strand break 2. The enzyme produce 3'OH termini suitable as

primers for DNA polymerase I3. The DNA polymerase I use 3'OH group as primer4. DNA polymerase I starts to synthesize a new

strand while displacing the DNA segment5. 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

Type III Repair Mechanism

Type III Repair Mechanism

STEPS TO MAKE MATHEMATICAL

MODEL FOR REPAIR SYSTEM

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

2. 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] k3

k-3 [3'OH][Pol I] k4 [ULDNA]+[Pol I]

[ULDNA]+[DNA ligase] k5 k-5 [ULDNA][DNA ligase] k6 [RDNA] +[DNA ligase]

3. Find the numerical values of the parameters of the chosen DNA repair system

Numerical values of the model parameters for type III

Parametersvalue

k1

k-1 k2

k3

k4

k-4

k5

11.977 sec-1

0.0627 sec-1

16.7sec-1

16.7sec-1

0.0335sec-1

0.0026sec-1

0.03sec-1

4. Construct a mathematical model of the chosen DNA repair system using the deterministic and stochastic approaches.

Input cv ( v=1,…,M) initi . Of Xi (i=1,…,N)Set t=0 & n=0Generate random numbers r1 and r2

Calculate a1= hvcv ( v=1,…,M)a0 = av

• Update t = t + • Update X = [X1, X2, …XC]• Update n= n + 1

Generate random numbers r1 and r2

Take

Entire Simulation

Gillespie,1976

5. Obtain and analyze solutions of the proposed model.

DNA Ligase

Complex between un legated DNA and Ligase

Repaired DNA

Type I Repair

RESULTS

Type II Repair

DNA Ligase

Complex between un legated DNA and Ligase

Complex between break DNA and polymerase

Repaired DNA

DNA polymerase I

RESULTS

DNA Ligase

DNA polymerase I

DNA exonuclease III

Type III Repair

RESULTS

Complex between un legated DNA and Ligase

Complex between break DNA and polymerase

Complex between break DNA and exonuclease iii

Repaired DNA

Type III Repair

RESULTS

Type I Repair Type II Repair

Type III Repair

Comparison between DNA ligase kineticks in different type of repair

Type II Repair Type III Repair

Comparison between DNA polymerase I kineticks in different type of repair

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

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)

AcknowledgementsFirstly 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