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Damage to cellular DNA from particulate radiations, the efficacy of its processing and the radiosensitivity of mammalian cells

Emphasis on DNA double strand breaks and chromatin breaks

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Summary

For several years, it has been evident that cellular radiation biology is in a necessary period of consolidation and transition (Lett 1987, 1990; Lett et al. 1986, 1987). Both changes are moving apace, and have been stimulated by studies with heavy charged particles.

From the standpoint of radiation chemistry, there is now a consensus of opinion that the DNA hydration shell must be distinguished from bulk water in the cell nucleus and treated as an integral part of DNA (chromatin) (Lett 1987). Concomitantly, sentiment is strengthening for the abandonment of the classical notions of “direct” and “indirect” action (Fielden and O'Neill 1991; O'Neill 1991; O'Neill et al. 1991; Schulte-Frohlinde and Bothe 1991 and references therein). A layer of water molecules outside, or in the outer edge of, the DNA (chromatin) hydration shell influences cellular radiosensitivity in ways not fully understood. Charge and energy transfer processes facilitated by, or involving, DNA hydration must be considered in rigorous theories of radiation action on cells. The induction and processing of double stand breaks (DSBs) in DNA (chromatin) seem to be the predominant determinants of the radiotoxicity of normally radioresistant mammalian cells, the survival curves of which reflect the patterns of damage induced and the damage present after processing ceases, and can be modelled in formal terms by the use of reaction (enzyme) kinetics. Incongruities such as sublethal damage are neither scientifically sound nor relevant to cellular radiation biology (Calkins 1991; Lett 1990; Lett et al. 1987a).

Increases in linear energy transfer (LET∞) up to 100–200 keV µm−1 cause increases in the extents of neighboring chemical and physical damage in DNA denoted by the general term DSB. Those changes are accompanied by decreasing abilities of cells normally radioresistant to sparsely ionizing radiations to process DSBs in DNA and chromatin and to recover from radiation exposure, so they make significant contributions to the relative biological effectiveness (RBE) of a given radiation. As the LET∞ is raised above a few hundred keV µm−1, the damage associated with DSBs continues to increase, but the efficiency of DSB induction declines to low values (∼0.1), as do RBE and the effective processing of DSBs and chromatin breaks, and the decline in RBE seems to mimic the overall decline in suitable processing of DSBs. Hence, the quality factor (Q) for a given radiation cannot be based solely upon the pattern of energy deposition, a fact attested to also by the quite different RBE responses exhibited by repair-deficient mutant (or variant) cells.

Understanding of the biological effects of heavy ions is important not only for the welfare of astronauts who will undertake extended interplanetary missions in space but also for the facilitation of a rigorous scientific basis for conventional radiation therapy.

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  1. Department of Radiological Health Sciences, Colorado State University, 80523, Fort Collins, CO, USA

    John T. Lett

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Based on a review lecture delivered at the Fourth Workshop on Heavy Charged Particles in Biology and Medicine, GSl, Darmstadt, Germany, September 1991. A number of scientists, see Acknowledgements, also gave unreservedly of their time at the 40th Annual Meeting of the Radiation Research Society, Salt Lake City, Utah, March 1992, to discuss topics in this article with the author

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Lett, J.T. Damage to cellular DNA from particulate radiations, the efficacy of its processing and the radiosensitivity of mammalian cells. Radiat Environ Biophys 31, 257–277 (1992). https://doi.org/10.1007/BF01210207

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