Modelling and calculation of DNA damage and repair in mammalian cells induced by ionizing radiation of different quality
Author: Taleei, Reza
Date: 2013-06-12
Location: CCK Seminar Room R8:00, Karolinska Institutet, Solna.
Time: 12.00
Department: Inst för onkologi-patologi / Dept of Oncology-Pathology
Abstract
Recent experimental data have revealed a wealth of information that provides an exceptional opportunity to construct a mechanistic model of DNA repair. The cellular response to radiation exposure starts with repair of DNA damage and cell signalling that may lead to mutation, or cell death. The purpose of this work was to construct a mechanistic mathematical model of DNA repair in mammalian cells. The repair model is based on biochemical action of repair proteins to examine the hypotheses regarding two or more components of double strand break (DSB) repair kinetics.
The mechanistic mathematical model of repair proposed in this thesis is part of a bottom-up approach that assumes the cell is a complex system. In this approach radiation induces DNA damage, and the cellular response to radiation perturbation was modelled in terms of activating repair processes. A biochemical kinetic method based on law of mass action was employed to model the repair pathways. The repair model consists of a set of nonlinear differential equations that calculates and explains protein activity on the damage step by step. The model takes into account complexity of the DSB, topology of damage in the cell nucleus, and cell cycle.
The solution of the model in terms of overall kinetics of DSB repair was compared with pulsed-field gel electrophoresis measurements. The repair model was integrated with the track structure model to calculate the damage spectrum and repair kinetics for every individual DSB induced by monoenergetic electrons, and ultrasoft X-rays. For this purpose we proposed a method to sample the protein repair actions for every individual DSB, and finally calculate the total repair time for that specific DSB. The DSB-repair kinetics for the number of DSB induced by 500 tracks of monoenergetic electrons and ultrasoft X-rays were calculated and compared with experimental results for cells irradiated with AlK, CK, and TiK ultrasoft X-rays.
The results presented here form the first example of mechanistic modelling and calculations for NHEJ, HR and MMEJ repair pathways. The results, for the first time, quantitatively confirm the hypothesis that the complex type double strand breaks play a major role in the slow kinetics of DSB repair. The results also confirm that simple DSB located in the heterocromatin delay the repair process due to a series of processes that are required for the relaxation of the heterochromatin. The repair model established in this work provides a unique opportunity to continue this study of cellular responses to radiation further downstream that may have important implications for human risk estimation and radiotherapy.
The mechanistic mathematical model of repair proposed in this thesis is part of a bottom-up approach that assumes the cell is a complex system. In this approach radiation induces DNA damage, and the cellular response to radiation perturbation was modelled in terms of activating repair processes. A biochemical kinetic method based on law of mass action was employed to model the repair pathways. The repair model consists of a set of nonlinear differential equations that calculates and explains protein activity on the damage step by step. The model takes into account complexity of the DSB, topology of damage in the cell nucleus, and cell cycle.
The solution of the model in terms of overall kinetics of DSB repair was compared with pulsed-field gel electrophoresis measurements. The repair model was integrated with the track structure model to calculate the damage spectrum and repair kinetics for every individual DSB induced by monoenergetic electrons, and ultrasoft X-rays. For this purpose we proposed a method to sample the protein repair actions for every individual DSB, and finally calculate the total repair time for that specific DSB. The DSB-repair kinetics for the number of DSB induced by 500 tracks of monoenergetic electrons and ultrasoft X-rays were calculated and compared with experimental results for cells irradiated with AlK, CK, and TiK ultrasoft X-rays.
The results presented here form the first example of mechanistic modelling and calculations for NHEJ, HR and MMEJ repair pathways. The results, for the first time, quantitatively confirm the hypothesis that the complex type double strand breaks play a major role in the slow kinetics of DSB repair. The results also confirm that simple DSB located in the heterocromatin delay the repair process due to a series of processes that are required for the relaxation of the heterochromatin. The repair model established in this work provides a unique opportunity to continue this study of cellular responses to radiation further downstream that may have important implications for human risk estimation and radiotherapy.
List of papers:
I. Taleei R, Nikjoo H. (2013). Biochemical DSB-Repair Model for Mammalian Cells in G1 and Early Phases of the Cell Cycle. Mutation Research. [Accepted]
Pubmed
View record in Web of Science®
II. Taleei R, Nikjoo H. (2013). The Nonhomologous End-Joining (NHEJ) Pathway for the Repair of DNA Double-Strand Breaks: I-A Mathematical Model. Radiation Research. 179: 530-9.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Taleei R, Girard P M, Sankaranarayanan K, Nikjoo H. (2013). The Nonhomologous End-Joining (NHEJ) Mathematica lModel for the Repair of Double-Strand Breaks: II-Application to Damage Induced by Ultrasoft X-Rays and Low Energy Electrons. Radiation Research. 179: 540-8.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Taleei R, Nikjoo H. (2012). Repair of the Double-Strand Breaks Induced by Low Energy Electrons: A Modelling Approach. International Journal of Radiation Biology. 88(12): 948-53.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Taleei R, Weinfeld M, Nikjoo H. (2011). A Kinetic Model of Single-Strand Annealing for the Repair of DNA Double-Strand Breaks. Radiation Protection Dosimetry. 143(2-4): 191-5.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Taleei R, Nikjoo H. (2013). Biochemical DSB-Repair Model for Mammalian Cells in G1 and Early Phases of the Cell Cycle. Mutation Research. [Accepted]
Pubmed
View record in Web of Science®
II. Taleei R, Nikjoo H. (2013). The Nonhomologous End-Joining (NHEJ) Pathway for the Repair of DNA Double-Strand Breaks: I-A Mathematical Model. Radiation Research. 179: 530-9.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Taleei R, Girard P M, Sankaranarayanan K, Nikjoo H. (2013). The Nonhomologous End-Joining (NHEJ) Mathematica lModel for the Repair of Double-Strand Breaks: II-Application to Damage Induced by Ultrasoft X-Rays and Low Energy Electrons. Radiation Research. 179: 540-8.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Taleei R, Nikjoo H. (2012). Repair of the Double-Strand Breaks Induced by Low Energy Electrons: A Modelling Approach. International Journal of Radiation Biology. 88(12): 948-53.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Taleei R, Weinfeld M, Nikjoo H. (2011). A Kinetic Model of Single-Strand Annealing for the Repair of DNA Double-Strand Breaks. Radiation Protection Dosimetry. 143(2-4): 191-5.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Hooshang, Nikjoo
Issue date: 2013-05-21
Rights:
Publication year: 2013
ISBN: 978-91-7549-189-9
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