Clustered DNA Damage and its Complexity: Tracking the History.

The concept of radiation-induced clustered damage in DNA has grown over the past several decades to become a topic of considerable interest across the scientific disciplines involved in studies of the biological effects of ionizing radiation. This paper, prepared for the 70th anniversary issue of Radiation Research, traces historical development of the three main threads of physics, chemistry, and biochemical/cellular responses that led to the hypothesis and demonstration that a key component of the biological effectiveness of ionizing radiation is its characteristic of producing clustered DNA damage of varying complexities. The physics thread has roots that started as early as the 1920s, grew to identify critical nanometre-scale clusterings of ionizations relevant to biological effectiveness, and then, by the turn of the century, had produced an extensive array of quantitative predictions on the complexity of clustered DNA damage from different radiations. Monte Carlo track structure simulation techniques played a key role through these developments, and they are now incorporated into many recent and ongoing studies modelling the effects of radiation. The chemistry thread was seeded by water-radiolysis descriptions of events in water as radical-containing "spurs," demonstration of the important role of the hydroxyl radical in radiation-inactivation of cells and the difficulty of protection by radical scavengers. This led to the concept and description of locally multiply damaged sites (LMDS) for DNA double-strand breaks and other combinations of DNA base damage and strand breakage that could arise from a spur overlapping, or created in very close proximity to, the DNA. In these ways, both the physics and the chemistry threads, largely in parallel, put out the challenge to the experimental research community to verify these predictions of clustered DNA damage from ionizing radiations and to investigate their relevance to DNA repair and subsequent cellular effects. The third thread, biochemical and cell-based research, responded strongly to the challenge by demonstrating the existence and biological importance of clustered DNA damage. Investigations have included repair of a wide variety of defined constructs of clustered damage, evaluation of mutagenic consequences, identification of clustered base-damage within irradiated cells, and identification of co-localization of repair complexes indicative of complex clustered damage after high-LET irradiation, as well as extensive studies of the repair pathways involved in repair of simple double-strand breaks. There remains, however, a great deal more to be learned because of the diversity of clustered DNA damage and of the biological responses.