Skip to main content
Log in

A Stochastic Model of DNA Double-Strand Breaks Repair Throughout the Cell Cycle

  • Original Article
  • Published:
Bulletin of Mathematical Biology Aims and scope Submit manuscript

Abstract

Cell cycle phase is a decisive factor in determining the repair pathway of DNA double-strand breaks (DSBs) by non-homologous end joining (NHEJ) or homologous recombination (HR). Recent experimental studies revealed that 53BP1 and BRCA1 are the key mediators of the DNA damage response (DDR) with antagonizing roles in choosing the appropriate DSB repair pathway in G1, S, and G2 phases. Here, we present a stochastic model of biochemical kinetics involved in detecting and repairing DNA DSBs induced by ionizing radiation during the cell cycle progression. A three-dimensional stochastic process is defined to monitor the cell cycle phase and DSBs repair at times after irradiation. To estimate the model parameters, a Metropolis Monte Carlo method is applied to perform maximum likelihood estimation utilizing the kinetics of γ-H2AX and RAD51 foci formation in G1, S, and G2 phases. The recruitment of DSB repair proteins is verified by comparing our model predictions with the corresponding experimental data on human cells after exposure to X and γ-radiation. Furthermore, the interaction between 53BP1 and BRCA1 is simulated for G1 and S/G2 phases determining the competition between NHEJ and HR pathways in repairing induced DSBs throughout the cell cycle. In accordance with recent biological data, the numerical results demonstrate that the maximum proportion of HR occurs in S phase cells and the high level of NHEJ takes place in G1 and G2 phases. Moreover, the stochastic realizations of the total yield of simple and complex DSBs ligation are compared for G1 and S/G2 damaged cells. Finally, the proposed stochastic model is validated when DSBs induced by different particle radiation such as iron, silicon, oxygen, proton, and carbon.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

References

  • Aparicio T, Baer R, Gautier J (2014) DNA double-strand break repair pathway choice and cancer. DNA Repair 19:169–175

    Google Scholar 

  • Asaithamby A, Chen DJ (2009) Cellular responses to DNA double-strand breaks after low-dose γ-irradiation. Nucleic Acids Res 37(12):3912–3923

    Google Scholar 

  • Asaithamby A, Uematsu N, Chatterjee A, Story MD, Burma S, Chen DJ (2008) Repair of HZE-particle-induced DNA double-strand breaks in normal human fibroblasts. Radiat Res 169(4):437–446

    Google Scholar 

  • Bee L, Fabris S, Cherubini R, Mognato M, Celotti L (2013) The efficiency of homologous recombination and non-homologous end joining systems in repairing double-strand breaks during cell cycle progression. PLoS ONE 8(7):e69061

    Google Scholar 

  • Belov OV, Krasavin EA, Lyashko MS, Batmunkh M, Sweilam NH (2015) A quantitative model of the major pathways for radiation-induced DNA double-strand break repair. J Theor Biol 366:115–130

    MathSciNet  MATH  Google Scholar 

  • Beucher A, Birraux J, Tchouandong L, Barton O, Shibata A, Conrad S, Goodarzi AA, Krempler A, Jeggo PA, Löbrich M (2009) ATM and Artemis promote homologous recombination of radiation-induced DNA double-strand breaks in G2. EMBO J 28(21):3413–3427

    Google Scholar 

  • Branzei D, Foiani M (2008) Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol 9(4):297

    Google Scholar 

  • Brzostek A, Szulc I, Klink M, Brzezinska M, Sulowska Z, Dziadek J (2014) Either non-homologous ends joining or homologous recombination is required to repair double-strand breaks in the genome of macrophage-internalized Mycobacterium tuberculosis. PLoS ONE 9:e92799

    Google Scholar 

  • Cucinotta FA, Pluth JM, Anderson JA, Harper JV, O’Neill P (2008) Biochemical kinetics model of DSB repair and induction of Î3-H2AX foci by non-homologous end joining. Radiat Res 169:214–222

    Google Scholar 

  • Daley JM, Sung P (2013) RIF1 in DNA break repair pathway choice. Mol Cell 49(5):840–841

    Google Scholar 

  • Daley JM, Sung P (2014) 53BP1, BRCA1, and the choice between recombination and end joining at DNA double-strand breaks. Mol Cell Biol 34(8):1380–1388

    Google Scholar 

  • Escribano-Díaz C, Orthwein A, Fradet-Turcotte A, Xing M, Young JT, Tkáč J et al (2013) A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. Mol Cell 49(5):872–883

    Google Scholar 

  • Feng L, Li N, Li Y, Wang J, Gao M, Wang W, Chen J (2015) Cell cycle-dependent inhibition of 53BP1 signaling by BRCA1. Cell Discov 1:15019

    Google Scholar 

  • Forment JV, Kaidi A, Jackson SP (2012) Chromothripsis and cancer: causes and consequences of chromosome shattering. Nat Rev Cancer 12(10):663

    Google Scholar 

  • Fowler TL, Bailey AM, Bednarz BP, Kimple RJ (2014) High-throughput detection of DNA double-strand breaks using image cytometry. Biotechniques 58(1):37

    Google Scholar 

  • Guo X, Bai Y, Zhao M, Zhou M, Shen Q, Yun CH, Zhang H, Zhu WG, Wang J (2017) Acetylation of 53BP1 dictates the DNA double strand break repair pathway. Nucleic Acids Res 46(2):689–703

    Google Scholar 

  • Gupta A, Hunt CR, Chakraborty S, Pandita RK, Yordy J, Ramnarain DB, Horikoshi N, Pandita TK (2013) Role of 53BP1 in the regulation of DNA double-strand break repair pathway choice. Radiat Res 181(1):1–8

    Google Scholar 

  • Gupta A, Hunt CR, Hegde ML, Chakraborty S, Udayakumar D, Horikoshi N, Singh M, Ramnarain DB, Hittelman WN, Namjoshi S, Asaithamby A (2014) MOF phosphorylation by ATM regulates 53BP1-mediated double-strand break repair pathway choice. Cell Rep 8(1):177–189

    Google Scholar 

  • Ivashkevich A, Redon CE, Nakamura AJ, Martin RF, Martin OA (2012) Use of the γ-H2AX assay to monitor DNA damage and repair in translational cancer research. Cancer Lett 327(1):123–133

    Google Scholar 

  • Iwamoto K, Hamada H, Eguchi Y, Okamoto M (2014) Stochasticity of intranuclear biochemical reaction processes controls the final decision of cell fate associated with DNA damage. PLoS ONE 9:e101333

    Google Scholar 

  • Jackson SP, Bartek J (2009) The DNA-damage response in human biology and disease. Nature 461(7267):1071

    Google Scholar 

  • Kakarougkas A, Jeggo PA (2014) DNA DSB repair pathway choice: an orchestrated handover mechanism. Brit J Radiol 87(1035):20130685

    Google Scholar 

  • Karanam K, Kafri R, Loewer A, Lahav G (2012) Quantitative live cell imaging reveals a gradual shift between DNA repair mechanisms and a maximal use of HR in mid S phase. Mol Cell 47(2):320–329

    Google Scholar 

  • Khalil H, Tummala H, Zhelev N (2012) ATM in focus: a damage sensor and cancer target. Biodiscovery 5:1

    Google Scholar 

  • Koury E, Harrell K, Smolikove S (2017) Differential RPA-1 and RAD-51 recruitment in vivo throughout the C. elegans germline, as revealed by laser microirradiation. Nucleic Acids Res 46(2):748–764

    Google Scholar 

  • Kurosawa A, Saito S, So S, Hashimoto M, Iwabuchi K, Watabe H et al (2013) DNA ligase IV and artemis act cooperatively to suppress homologous recombination in human cells: implications for DNA double-strand break repair. PLoS ONE 8:e72253

    Google Scholar 

  • Li Y, Cucinotta FA (2011) Modeling non-homologous end joining. J Theor Biol 283:122–135

    MathSciNet  MATH  Google Scholar 

  • Li X, Heyer WD (2008) Homologous recombination in DNA repair and DNA damage tolerance. Cell Res 18(1):99

    Google Scholar 

  • Li Y, Reynolds P, O’Neill P, Cucinotta FA (2014) Modeling damage complexity-dependent non-homologous end-joining repair pathway. PLoS ONE 9:e85816

    Google Scholar 

  • Löbrich M, Cooper PK, Rydberg B (1998) Joining of correct and incorrect DNA ends at double-strand breaks produced by high-linear energy transfer radiation in human fibroblasts. Radiat Res 150:619–626

    Google Scholar 

  • Löbrich M, Shibata A, Beucher A, Fisher A, Ensminger M, Goodarzi AA, Barton O, Jeggo PA (2010) γH2AX foci analysis for monitoring DNA double-strand break repair: strengths, limitations and optimization. Cell Cycle 9(4):662–669

    Google Scholar 

  • Lord CJ, Ashworth A (2012) The DNA damage response and cancer therapy. Nature 481(7381):287

    Google Scholar 

  • Mariotti LG, Pirovano G, Savage KI, Ghita M, Ottolenghi A, Prise KM, Schettino G (2013) Use of the γ-H2AX assay to investigate DNA repair dynamics following multiple radiation exposures. PLoS ONE 8(11):e79541

    Google Scholar 

  • Mohseni-Salehi FS, Zare-Mirakabad F, Ghafouri-Fard S, Sadeghi M (2017) The effect of stochasticity on repair of DNA double strand breaks throughout non-homologous end joining pathway. Math Med Biol J IMA 35:517–539

    MathSciNet  MATH  Google Scholar 

  • Mouri K, Nacher JC, Akutsu T (2009) A mathematical model for the detection mechanism of DNA double-strand breaks depending on autophosphorylation of ATM. PLoS ONE 4(4):e5131

    Google Scholar 

  • Ogiwara H, Kohno T (2011) Essential factors for incompatible DNA end joining at chromosomal DNA double strand breaks in vivo. PLoS ONE 6:e28756

    Google Scholar 

  • Plante I, Ponomarev AL, Cucinotta FA (2013) Calculation of the energy deposition in nanovolumes by protons and HZE particles: geometric patterns of initial distributions of DNA repair foci. Phys Med Biol 58(18):6393

    Google Scholar 

  • Reid DA, Conlin MP, Yin Y, Chang HH, Watanabe G, Lieber MR, Ramsden DA, Rothenberg E (2016) Bridging of double-stranded breaks by the nonhomologous end-joining ligation complex is modulated by DNA end chemistry. Nucleic Acids Res 45(4):1872–1878

    Google Scholar 

  • Saleh-Gohari N, Helleday T (2004) Conservative homologous recombination preferentially repairs DNA double-strand breaks in the S phase of the cell cycle in human cells. Nucleic Acids Res 32:3683–3688

    Google Scholar 

  • Sastre-Moreno G, Pryor JM, Díaz-Talavera A, Ruiz JF, Ramsden DA, Blanco L (2017) Polμ tumor variants decrease the efficiency and accuracy of NHEJ. Nucleic Acids Res 45(17):10018–10031

    Google Scholar 

  • Shibata A, Conrad S, Birraux J, Geuting V, Barton O, Ismail A, Kakarougkas A, Meek K, Taucher-Scholz G, Löbrich M, Jeggo PA (2011) Factors determining DNA double-strand break repair pathway choice in G2 phase. EMBO J 30(6):1079–1092

    Google Scholar 

  • Srivastava S, Dahal S, Naidu SJ, Anand D, Gopalakrishnan V, Kooloth Valappil R, Raghavan SC (2017) DNA double-strand break repair in Penaeus monodon is predominantly dependent on homologous recombination. DNA Res 24(2):117–128

    Google Scholar 

  • Sung P, Klein H (2006) Mechanism of homologous recombination: mediators and helicases take on regulatory functions. Nat Rev Mol Cell Biol 7(10):739

    Google Scholar 

  • Taleei R (2019) Modelling DSB repair kinetics for DNA damage induced by proton and carbon ions. Radiat Prot Dosim 183:75–78

    Google Scholar 

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

    Google Scholar 

  • Taleei R, Girard PM, Sankaranarayanan K, Nikjoo H (2013) The non-homologous end-joining (NHEJ) mathematical model for the repair of double-strand breaks: II. Application to damage induced by ultrasoft X rays and low-energy electrons. Radiat Res 179(5):540–548

    Google Scholar 

  • Tomlin CJ, Axelrod JD (2007) Biology by numbers: mathematical modelling in developmental biology. Nat Rev Genet 8(5):331

    Google Scholar 

  • Uziel T, Lerenthal Y, Moyal L, Andegeko Y, Mittelman L, Shiloh Y (2003) Requirement of the MRN complex for ATM activation by DNA damage. EMBO J 22(20):5612–5621

    Google Scholar 

  • West RB, Yaneva M, Lieber MR (1998) Productive and nonproductive complexes of Ku and DNA-dependent protein kinase at DNA termini. Mol Cell Biol 18:5908–5920

    Google Scholar 

  • Zhang H, Liu H, Chen Y, Yang X, Wang P, Liu T et al (2016) A cell cycle-dependent BRCA1–UHRF1 cascade regulates DNA double-strand break repair pathway choice. Nat Commun 7:10201

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Fatemeh Zare-Mirakabad.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (EPS 34 kb)

Supplementary material 2 (EPS 66 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mohseni-Salehi, F.S., Zare-Mirakabad, F., Sadeghi, M. et al. A Stochastic Model of DNA Double-Strand Breaks Repair Throughout the Cell Cycle. Bull Math Biol 82, 11 (2020). https://doi.org/10.1007/s11538-019-00692-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11538-019-00692-z

Keywords

Navigation