A Simplified Cluster Analysis of Electron Track Structure for Estimating Complex DNA Damage Yields.

Yusuke Matsuya,Toshiaki Nakano,Ken Akamatsu,Tatsuhiko Sato,Yuji Yoshii,Takeshi Kai,Naoya Shikazono

doi:10.3390/ijms21051701

Abstract

Complex DNA damage, defined as at least two vicinal lesions within 10–20 base pairs (bp), induced after exposure to ionizing radiation, is recognized as fatal damage to human tissue. Due to the difficulty of directly measuring the aggregation of DNA damage at the nano-meter scale, many cluster analyses of inelastic interactions based on Monte Carlo simulation for radiation track structure in liquid water have been conducted to evaluate DNA damage. Meanwhile, the experimental technique to detect complex DNA damage has evolved in recent decades, so both approaches with simulation and experiment get used for investigating complex DNA damage. During this study, we propose a simplified cluster analysis of ionization and electronic excitation events within 10 bp based on track structure for estimating complex DNA damage yields for electron and X-ray irradiations. We then compare the computational results with the experimental complex DNA damage coupled with base damage (BD) measured by enzymatic cleavage and atomic force microscopy (AFM). The computational results agree well with experimental fractions of complex damage yields, i.e., single and double strand breaks (SSBs, DSBs) and complex BD, when the yield ratio of BD/SSB is assumed to be 1.3. Considering the comparison of complex DSB yields, i.e., DSB + BD and DSB + 2BD, between simulation and experimental data, we find that the aggregation degree of the events along electron tracks reflects the complexity of induced DNA damage, showing 43.5% of DSB induced after 70 kVp X-ray irradiation can be classified as a complex form coupled with BD. The present simulation enables us to quantify the type of complex damage which cannot be measured through in vitro experiments and helps us to interpret the experimental detection efficiency for complex BD measured by AFM. This simple model for estimating complex DNA damage yields contributes to the precise understanding of the DNA damage complexity induced after X-ray and electron irradiations.

Highlights

Ionizing radiation within the human body causes DNA damage [1] both physically [2,3] and chemically reacting to the DNA target [4,5,6,7]
The structure of complex DNA damage, i.e., the number of lesions per damaged site was recently revealed with atomic force microscopy (AFM), where an individual base damage (BD) in a complex damage site is labelled with biotin/avidin coupled with an aldehyde reactive probe (ARP) [41]
Regarding the case of η = 1.0, the simulation was in better agreement with the experimental data [41] than the estimated value with η = 0.9, proving that the efficiency for detecting BD under atomic force microscopy (AFM) operation is over 90% which is consistent with the experimental efficiency [41]

Summary

Introduction

Ionizing radiation within the human body causes DNA damage [1] both physically (i.e., energy deposition) [2,3] and chemically (i.e., free radical) reacting to the DNA target [4,5,6,7]. DNA damage types [8,9], DNA double-strand breaks (DSBs), defined as two strand breaks within 10 base pairs (bp) [2,10,11] are conventionally recognized as fatal DNA damage, which can lead to cell death with a certain probability [12]. Complex DNA damage composed of at least three vicinal lesions caused within 10–20 bp, such as DSBs coupled with strand breaks or base damage (BD), is believed to be more lethal to cells than simple DSBs [20,21] due to refractory damage [22,23]. Due to the difficulty of measuring complex DNA damage, the validity of simulations has not been sufficiently demonstrated yet

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Conclusion