Abstract
Ionizing radiation damages DNA and also induces oxidative stress, which can affect the function of proteins involved in DNA repair, thereby causing repair of DNA damage to become less efficient. We previously developed a mathematical model of this potentially synergistic relationship and applied it to γ-ray exposure data on the radiation-resistant prokaryote Deinococcus radiodurans. Here, we investigate the effects of radiation quality on these processes by applying the model to data on exposures of D. radiodurans to heavy ions with linear energy transfer (LET) of 18.5–11,300 keV/μm. The model adequately describes these data using three parameters combinations: radiogenic DNA damage induction, repair protein inactivation and cellular repair capacity. Although statistical uncertainties around best-fit parameter estimates are substantial, the behaviors of model parameters are consistent with current knowledge of LET effects: inactivation cross-sections for both DNA and proteins increase with increasing LET; DNA damage yield per unit of radiation dose also increases with LET; protein damage per unit dose tends to decrease with LET; DNA and especially protein damage yields are reduced when cells are irradiated in the dry state. These results suggest that synergism between oxidative stress and DNA damage may play an important role not only during γ-ray exposure, but during high-LET radiation exposure as well.
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Research supported by National Institutes of Health grants P41 EB002033-09 and P01 CA-49062.
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Appendix
Appendix
In this appendix we explore some properties of the behavior of predicted cell surviving fraction after acute irradiation (S), given by (3) of the main text. To do so, we apply some limiting cases described below.
Effect of repair protein inactivation (k 1)
The model assumes that DSB repair in D. radiodurans is inherently 100% efficient, but that this efficiency is reduced by radiogenic inactivation of repair proteins (parameter k 1), and also by limitations on protein turnover rates, repair rates, and time available for repair (affecting parameter k 23). At relatively small radiation doses (D ≪ 1/k 1), most of the repair proteins remain functional and DSB repair remains very efficient. In this situation the term exp[−k 1 D] in (3) is approximately equal to 1, so the cell-surviving fraction has the form:
Here, the reduction of cell survival with dose is exponential, but this exponential slope is much smaller than the maximum it could reach (which would be equal to the DSB induction rate per unit dose, c 8) by the factor exp[−k 23]. The DSB repair efficiency could be approximated by 1 − exp[−k 23].
In contrast, at much larger radiation doses (D ≫ 1/k 1), the term exp{−k 1 D} in (3) approaches zero, so the cell surviving fraction becomes:
Consequently, at high doses the exponential slope approaches the DSB induction rate per unit dose (c 8), meaning that efficiency of DSB repair is reduced essentially to zero.
Effect of repair capacity (k 23)
If the repair-related parameter k 23 approaches zero, e.g. due to genetic repair defects, the term exp[−k 23 exp{−k 1 D}] in (3) becomes 1, and the exponential slope of the cell survival curve reaches the value c 8. In contrast, if k 23 become large, this term becomes small, making the exponential slope ≪ c 8, as intuitively expected.
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Shuryak, I., Brenner, D.J. Effects of radiation quality on interactions between oxidative stress, protein and DNA damage in Deinococcus radiodurans . Radiat Environ Biophys 49, 693–703 (2010). https://doi.org/10.1007/s00411-010-0305-1
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DOI: https://doi.org/10.1007/s00411-010-0305-1