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

Abstract

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 infinity) up to 100-200 keV micron-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.(ABSTRACT TRUNCATED AT 400 WORDS)

ATM, a central controller of cellular responses to DNA damage

“…21 It seems likely that residual breaks are signalled to the repair machinery in an ATM-dependent manner and therefore they remain unrepaired in A-T cells and, as a consequence, translate into chromosome breaks. DSBs appear in DNA as a consequence of exposure to IR and other DNA damaging agents, 22 in response to blocked DNA replication forks 23 and during normal biological processes such as T and B cell differentiation and meiosis. 24,25 Therefore, it is not surprising that in syndromes such as A-T and NBS a defective response to radiation-induced breaks is also accompanied by abnormal processing of naturally occurring breaks.…”

The Effect of Packing and Conformation on Free Radical Yields in Films of Variably Hydrated DNA

“…The importance of hydration in the radiosensitivity of DNA has long been recognized (15)(16)(17). An understanding of the role of hydration in direct-type damage is necessary for an accurate quantification of the DNA target mass, which in turn is essential to predicting DNA damage in vivo.…”

Micronucleus induction and reproductive death in a human cell line exposed to low-energy argon beam

“…Further investigations are warranted to understand induction and processing of cell damage after particle irradiation better and to relate it to the local energy deposition (Lett 1992). It is likely that the MN assay provides a useful tool in this respect.…”