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Modeling the NHEJ repair of DNA damage induced by electrons calculated using the MCNPX and Geant4-DNA codes

Document Type : Research Paper

Authors

1 Department of Physics, Isfahan University of Technology, P.O.Box: 8415683111, Isfahan – Iran

2 Department of Physics, Behbahan Khatam Alanbia University of Technology, P.O.Box: 6361663973, Behbahan - Iran

Abstract

In radiotherapy, ionizing radiation is used to damage cells. Monte Carlo simulations of radiation interactions with DNA give us good information about the type of damage and their repair process, which can be very useful in treating cancer and protecting against radiation. The ionizing radiation damage includes single- and double-strand breaks as well as base lesions (SSB, DSB, BL). The DNA damage can be repaired through some processes within the cell. DNA damage, especially of DSBs that are mis-repaired or unrepaired, can result in cell death. This process plays a crucial role in killing cancer cells and treating cancer. In this research, first, the dose was calculated in the cell nucleus with the MCNPX code. Then, the possibility of different damage types in DNA was investigated by simulating the physical and chemical processes of low and high-energy electrons with the Geant4-DNA code. Then with the help of the Matlab software and mathematical modeling, we investigated the repair of DSBs for the latter energies. The results show that at ranging energies of 100 to 300 eV, the number of breaks increases, and for higher energies, it decreases due to the electron range in the cell nucleus. The repair reaction rate is also calculated from the NHEJ presynaptic process for ranging energies 100 eV to 1 MeV. In the repair section, the repair time at low energies is longer than the higher energies due to more DSBs.

Highlights

  1. E.B. Podgorsak, Radiation Oncology Physics: A Handbook for Teachers and Students, (International Atomic Energy Agency, Vienna 2005).

 

  1. H. Ouyang, et al, Ku70 is required for DNA repair but not for T cell antigen receptor gene recombination in vivo, J. Exp. Med., 186, 921–929 (1997).

 

  1. M. Lobrich, P.A. Jeggo, Harmonising the response to DSBs: a new string in the ATM bow, DNA Repair, 4, 749–759 (2005).

 

  1. H. Nikjoo, et al, Radiation track, DNA damage and response—a review, Rep. Prog. Phys., 79, 116601 (2016).

 

  1. L.S. Symington, J. Gautier, Double-strand break end resection and repair pathway choice, Annu. Rev. Genet., 45, 247–271 (2011).

 

  1. R. Taleei, P.M. Girard, H. Nikjoo, DSB repair model for mammalian cells in early S and G1 phases of the cell cycle: application to damage induced by ionizing radiation of different quality, Mutat. Res., 779, 5–14 (2015).

 

  1. C.M. De Lara, et al., Dependence of the Yield of DNA Double-strand Breaks in Chinese Hamster V79–4 Cells on the Photon Energy of Ultrasoft X Rays, Radiat. Res., 155, 440–448 (2001).

 

  1. M. Mokari, et al, Track structure simulation of low energy electron damage to DNA using Geant4-DNA, Biomed. Phys. Eng. Express, 4, 65009 (2018).

 

  1. R. Taleei, H. Nikjoo, Biochemical DSB-repair model for mammalian cells in G1 and early S phases of the cell cycle, Mutat. Res., 756, 206–12 (2013).

 

  1. P. Kundrát, R.D. Stewart, On the biophysical interpretation of lethal DNA lesions induced by ionising radiation, Radiation Protection Dosimetry, 122, 169–172 (2006).

 

  1. F.A. Cucinotta, et al, Biochemical kinetics model of DSB repair and induction of gamma-H2AX foci by nonhomologous end joining, Radiat. Res., 169, 214–222 (2008).

 

  1. F.A. Cucinotta, et al, Kinetics of DSB rejoining and formation of simple chromosome exchange aberrations, Int. J. Radiat. Biol., 76, 1463–1474 (2000).

 

  1. R. Taleei, H. Nikjoo, The non-homologous end-joining (NHEJ) pathway for the repair of DNA double-strand breaks: I. A mathematical model, Radiat. Res., 179, 530–539 (2013).

 

  1. R. Taleei, et al, The non-homologous end-joining (NHEJ) pathway for the repair of DNA double-strand breaks: II. Application to damage induced by ultrasoft X-rays and low energy electrons, Radiat. Res., 179, 540–548 (2013).

 

  1. P. Reynolds, et al, The dynamics of Ku70/80 and DNA-PKcs at DSBs induced by ionizing radiation is dependent on the complexity of damage, Nucleic Acids Res., 40, 10821–10831 (2012).

 

  1. M. Wang, et al, PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways, Nucleic Acids Res., 34, 6170–6182 (2006).

 

  1. K. Meek, et al, Trans Autophosphorylation at DNA-dependent protein kinase’s two major autophosphorylation site clusters facilitates end processing but not end joining, Mol. Cell. Biol., 27, 3881–3890 (2007).

 

  1. A.A. Goodarzi, P. Jeggo, M. Lobrich, The influence of heterochromatin on DNA double strand break repair: getting the strong, silent type to relax, DNA Repair, 9, 1273–1282 (2010).

 

  1. M. Wang, et al, PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways, Nucleic Acids Res., 34, 6170–6182 (2006).

 

  1. L. Liang, et al, Modulation of DNA end joining by nuclear proteins, J. Biol. Chem., 280, 31442–31449 (2005).

 

  1. E. Crespan, et al, Microhomology-mediated DNA strand annealing and elongation by human DNA polymerases lambda and beta on normal and repetitive DNA sequences, Nucleic Acids Res., 40, 5577–5590 (2012).

 

  1. W. Friedland, et al, Track structures, DNA targets and radiation effects in the biophysical Monte Carlo simulation code PARTRAC, Mutat. Res., 711, 28–40 (2011).

 

  1. W. Friedland, P. Jacob, P. Kundrát, Stochastic simulation of DNA double-strand break repair by non-homologous end joining based on track structure calculations, Radiat. Res., 173, 677–88 (2010).

 

  1. S.P. Ingram, et al., Mechanistic modelling supports entwined rather than exclusively competitive DNA double-strand break repair pathway, Scientific Reports, 9, 6359 (2019).

 

  1. M. Mokari, et al, A Simulation Approach for Determining the Spectrum of DNA Damage Induced by Protons, Phys. Med. Biol., 63, 175003 (2018).

 

  1. M. Belli, et al, DNA DSB induction and rejoining in V79 cells irradiated with light ions: a constant field gel electrophoresis study, Int. J. Radiat. Biol., 76, 1095–1104 (2000).

Keywords

References
  1. E.B. Podgorsak, Radiation Oncology Physics: A Handbook for Teachers and Students, (International Atomic Energy Agency, Vienna 2005).

 

  1. H. Ouyang, et al, Ku70 is required for DNA repair but not for T cell antigen receptor gene recombination in vivo, J. Exp. Med., 186, 921–929 (1997).

 

  1. M. Lobrich, P.A. Jeggo, Harmonising the response to DSBs: a new string in the ATM bow, DNA Repair, 4, 749–759 (2005).

 

  1. H. Nikjoo, et al, Radiation track, DNA damage and response—a review, Rep. Prog. Phys., 79, 116601 (2016).

 

  1. L.S. Symington, J. Gautier, Double-strand break end resection and repair pathway choice, Annu. Rev. Genet., 45, 247–271 (2011).

 

  1. R. Taleei, P.M. Girard, H. Nikjoo, DSB repair model for mammalian cells in early S and G1 phases of the cell cycle: application to damage induced by ionizing radiation of different quality, Mutat. Res., 779, 5–14 (2015).

 

  1. C.M. De Lara, et al., Dependence of the Yield of DNA Double-strand Breaks in Chinese Hamster V79–4 Cells on the Photon Energy of Ultrasoft X Rays, Radiat. Res., 155, 440–448 (2001).

 

  1. M. Mokari, et al, Track structure simulation of low energy electron damage to DNA using Geant4-DNA, Biomed. Phys. Eng. Express, 4, 65009 (2018).

 

  1. R. Taleei, H. Nikjoo, Biochemical DSB-repair model for mammalian cells in G1 and early S phases of the cell cycle, Mutat. Res., 756, 206–12 (2013).

 

  1. P. Kundrát, R.D. Stewart, On the biophysical interpretation of lethal DNA lesions induced by ionising radiation, Radiation Protection Dosimetry, 122, 169–172 (2006).

 

  1. F.A. Cucinotta, et al, Biochemical kinetics model of DSB repair and induction of gamma-H2AX foci by nonhomologous end joining, Radiat. Res., 169, 214–222 (2008).

 

  1. F.A. Cucinotta, et al, Kinetics of DSB rejoining and formation of simple chromosome exchange aberrations, Int. J. Radiat. Biol., 76, 1463–1474 (2000).

 

  1. R. Taleei, H. Nikjoo, The non-homologous end-joining (NHEJ) pathway for the repair of DNA double-strand breaks: I. A mathematical model, Radiat. Res., 179, 530–539 (2013).

 

  1. R. Taleei, et al, The non-homologous end-joining (NHEJ) pathway for the repair of DNA double-strand breaks: II. Application to damage induced by ultrasoft X-rays and low energy electrons, Radiat. Res., 179, 540–548 (2013).

 

  1. P. Reynolds, et al, The dynamics of Ku70/80 and DNA-PKcs at DSBs induced by ionizing radiation is dependent on the complexity of damage, Nucleic Acids Res., 40, 10821–10831 (2012).

 

  1. M. Wang, et al, PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways, Nucleic Acids Res., 34, 6170–6182 (2006).

 

  1. K. Meek, et al, Trans Autophosphorylation at DNA-dependent protein kinase’s two major autophosphorylation site clusters facilitates end processing but not end joining, Mol. Cell. Biol., 27, 3881–3890 (2007).

 

  1. A.A. Goodarzi, P. Jeggo, M. Lobrich, The influence of heterochromatin on DNA double strand break repair: getting the strong, silent type to relax, DNA Repair, 9, 1273–1282 (2010).

 

  1. M. Wang, et al, PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways, Nucleic Acids Res., 34, 6170–6182 (2006).

 

  1. L. Liang, et al, Modulation of DNA end joining by nuclear proteins, J. Biol. Chem., 280, 31442–31449 (2005).

 

  1. E. Crespan, et al, Microhomology-mediated DNA strand annealing and elongation by human DNA polymerases lambda and beta on normal and repetitive DNA sequences, Nucleic Acids Res., 40, 5577–5590 (2012).

 

  1. W. Friedland, et al, Track structures, DNA targets and radiation effects in the biophysical Monte Carlo simulation code PARTRAC, Mutat. Res., 711, 28–40 (2011).

 

  1. W. Friedland, P. Jacob, P. Kundrát, Stochastic simulation of DNA double-strand break repair by non-homologous end joining based on track structure calculations, Radiat. Res., 173, 677–88 (2010).

 

  1. S.P. Ingram, et al., Mechanistic modelling supports entwined rather than exclusively competitive DNA double-strand break repair pathway, Scientific Reports, 9, 6359 (2019).

 

  1. M. Mokari, et al, A Simulation Approach for Determining the Spectrum of DNA Damage Induced by Protons, Phys. Med. Biol., 63, 175003 (2018).

 

  1. M. Belli, et al, DNA DSB induction and rejoining in V79 cells irradiated with light ions: a constant field gel electrophoresis study, Int. J. Radiat. Biol., 76, 1095–1104 (2000).
Journal of Nuclear Science, Engineering and Technology (JONSAT)
Volume 43, Issue 4 - Serial Number 102
December 2022
Pages 59-66
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