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.
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
Asaithamby A, Chen DJ (2009) Cellular responses to DNA double-strand breaks after low-dose γ-irradiation. Nucleic Acids Res 37(12):3912–3923
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
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
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
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
Branzei D, Foiani M (2008) Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol 9(4):297
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
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
Daley JM, Sung P (2013) RIF1 in DNA break repair pathway choice. Mol Cell 49(5):840–841
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
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
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
Forment JV, Kaidi A, Jackson SP (2012) Chromothripsis and cancer: causes and consequences of chromosome shattering. Nat Rev Cancer 12(10):663
Fowler TL, Bailey AM, Bednarz BP, Kimple RJ (2014) High-throughput detection of DNA double-strand breaks using image cytometry. Biotechniques 58(1):37
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
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
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
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
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
Jackson SP, Bartek J (2009) The DNA-damage response in human biology and disease. Nature 461(7267):1071
Kakarougkas A, Jeggo PA (2014) DNA DSB repair pathway choice: an orchestrated handover mechanism. Brit J Radiol 87(1035):20130685
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
Khalil H, Tummala H, Zhelev N (2012) ATM in focus: a damage sensor and cancer target. Biodiscovery 5:1
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
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
Li Y, Cucinotta FA (2011) Modeling non-homologous end joining. J Theor Biol 283:122–135
Li X, Heyer WD (2008) Homologous recombination in DNA repair and DNA damage tolerance. Cell Res 18(1):99
Li Y, Reynolds P, O’Neill P, Cucinotta FA (2014) Modeling damage complexity-dependent non-homologous end-joining repair pathway. PLoS ONE 9:e85816
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
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
Lord CJ, Ashworth A (2012) The DNA damage response and cancer therapy. Nature 481(7381):287
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
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
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
Ogiwara H, Kohno T (2011) Essential factors for incompatible DNA end joining at chromosomal DNA double strand breaks in vivo. PLoS ONE 6:e28756
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
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
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
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
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
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
Sung P, Klein H (2006) Mechanism of homologous recombination: mediators and helicases take on regulatory functions. Nat Rev Mol Cell Biol 7(10):739
Taleei R (2019) Modelling DSB repair kinetics for DNA damage induced by proton and carbon ions. Radiat Prot Dosim 183:75–78
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
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
Tomlin CJ, Axelrod JD (2007) Biology by numbers: mathematical modelling in developmental biology. Nat Rev Genet 8(5):331
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
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
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
Author information
Authors and Affiliations
Corresponding author
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.
Rights and permissions
About this article
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
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11538-019-00692-z