Radiation-induced DNA-damage simulation using computational methods

SCK•CEN Mentor

Parisi Alessio, aparisi@sckcen.be, +32 (0)14 33 28 08

Expert group

Research in Dosimetric Applications

Introduction

The effects of radiation on living entities are strongly related to the microscopic pattern of energy deposition at cellular and subcellular scale (Scholz, 2003), with the breaks in the strains of the deoxyribonucleic acid (DNA) currently considered as the initiator of those biological processes which will finally determine the consequences of exposures to different radiation qualities (i.e. chromosome aberration, mitotic catastrophe, apoptosis,  Goodhead, 1994). These DNA damages are generally classified in relation to their complexity (base damages BD, single strand breaks SSB, double strand breaks DSB and DSB clusters) and the physical/chemical pathways which caused them. As an example, DNA damages could originate from both the direct interaction of the radiation with the DNA strands (direct effects) or through the production or free radical species liberated by the radiation in the surrounding medium (indirect effects) (Nikjoo et al., 2016).

In order to provide an in-depth view of the cell damage processes, detailed computer radiation-transport Monte Carlo software called track structure codes (Nikjoo et al., 2006) were developed and employed for DNA-damage simulations. This is done by coupling a detailed description of the radiation-induced physical and chemical reactions at the nanoscale with a realistic description of the target volumes (i.e., DNA strands, chromosomes, nucleus, McNamara et al., 2018) and biophysical models able to relate the energy deposition and the production of radicals with the probability of DNA base damaging and strand breaks. Finally, the inherent the ability of the cells to fix these DNA damages should be taken into account by modeling the three main repair pathways (Nonhomologous End Joining - NHEJ, Homologous Recombination - HR, and Microhomology Mediated End Joining - MMEJ) according to their availability during the cell cycle of the considered biological entity (McMahon and Prise, 2019). The so-obtained distribution of residual DNA damages on higher structural levels (chromatin loops, chromosome territories, whole nucleus) is expected to relate with macroscopic effects such as chromosome aberrations and cell death.

 

Objective

With the increasing exposure of humans to densely ionizing radiation for space or hadron therapy applications, it is of fundamental importance to understand the multiscale radiation-induced effects for radioprotection and treatment planning purposes. Thus, this study will represent an important step in this process by assessing the radiation-induced DNA damage using computational tools for various exposure scenarios (electrons, photons, ions) and different target definition (entire cell nucleus, simple DNA string…). The calculations will be performed employing the computer codes TOPAS-nBIO (Schuemann et al., 2018) and MCDS (Semenenko and Stewart, 2004), and systematically investigating the effect of varying and co-varying the simulation parameters. The validation of the obtained results will be performed through a comparison against literature in vitro data and other track structure simulations.


Structure of the study

  1. Get familiar with the mechanisms underlying the radiation-induced damaging process at different scales and its effect on living entities (DNA damage and repair, chromosome aberrations, cell survival).
  1. Create a database of DNA-damage (SSB, DSB, DSB cluster…), DNA-repair and chromosome aberrations by extracting the results of published in vitro and in silico published studies. The database will later serve as a validation tool for the data obtained during this work.
  1. Perform the simulations of the initial DNA-damage using the TOPAS-nBIO and MCDS codes investigating the combined effect of varying:
    1. the radiation quality (electrons, photons and ions)
    2. the DNA damage scoring method (threshold or linear probability)
    3. the production of radical species
    4. the macro- and microscopic target definition
    5. the hypoxia level (oxygen availability within the target volume)
    6. the simulation code
  1. Validate the results against the initial-DNA damage data of point 2)
  1. Assess the performances of existing or ad hoc developed DNA repair models in comparison with the repair-kinetics data of point 2).
  1. Analyze the pattern of residual DNA damage in relation to their spatial distribution and the correlation with higher-level endpoints and DNA fragmentations, chromosome aberration and cell survival.
  1. Write a report/thesis

 

References

Goodhead, D.T., 1994. Initial events in the cellular effects of ionizing radiations: clustered damage in DNA. International journal of radiation biology, 65(1), pp.7-17.

McMahon, S.J. and Prise, K.M., 2019. Mechanistic modelling of radiation responses. Cancers, 11(2), p.205.

McNamara, A.L., Ramos-Méndez, J., Perl, J., Held, K., Dominguez, N., Moreno, E., Henthorn, N.T., Kirkby, K.J., Meylan, S., Villagrasa, C. and Incerti, S., 2018. Geometrical structures for radiation biology research as implemented in the TOPAS-nBio toolkit. Physics in Medicine & Biology, 63(17), p.175018.

Nikjoo, H., Uehara, S., Emfietzoglou, D. and Cucinotta, F.A., 2006. Track-structure codes in radiation research. Radiation Measurements, 41(9-10), pp.1052-1074.

Nikjoo, H., Emfietzoglou, D., Liamsuwan, T., Taleei, R., Liljequist, D. and Uehara, S., 2016. Radiation track, DNA damage and response—a review. Reports on Progress in Physics, 79(11), p.116601.

Scholz, M., 2003. Effects of ion radiation on cells and tissues. In Radiation effects on polymers for biological use (pp. 95-155). Springer, Berlin, Heidelberg.

Schuemann, J., McNamara, A.L., Ramos-Méndez, J., Perl, J., Held, K.D., Paganetti, H., Incerti, S. and Faddegon, B., 2018. TOPAS-nBio: An Extension to the TOPAS Simulation Toolkit for Cellular and Sub-cellular Radiobiology. Radiation research, 191(2), pp.125-138.

Semenenko, V.A. and Stewart, R.D., 2004. A fast Monte Carlo algorithm to simulate the spectrum of DNA damages formed by ionizing radiation. Radiation research, 161(4), pp.451-457.

 

The minimum diploma level of the candidate needs to be

Professional bachelor , Academic bachelor , Master of industrial sciences , Master of sciences , Master of sciences in engineering

The candidate needs to have a background in

Informatics , Physics