Radiation Track Structure: How the Spatial Distribution of Energy Deposition Drives Biological Response.

Ionising radiation is incredibly effective at causing biological effects. This is due to the unique way energy is deposited along highly structured tracks of ionisation and excitation events, which results in correlation with sites of DNA damage from the nanometre to the micrometre scale. Correlation of these events along the track on the nanometre scale results in clustered damage, which not only results in the formation of DNA double-strand breaks (DSB), but also more difficult to repair complex DSB, which include additional damage within a few base pairs. The track structure varies significantly with radiation quality and the increase in relative biological effectiveness observed with increasing linear energy transfer in part corresponds to an increase in the probability and complexity of clustered DNA damage produced. Likewise, correlation over larger scales, associated with packing of DNA and associated chromosomes within the cell nucleus, can also have a major impact on the biological response. The proximity of the correlated damage along the track increases the probability of miss-repair through pairwise interactions resulting in an increase in probability and complexity of DNA fragments/deletions, mutations and chromosomal rearrangements. Understanding the mechanisms underlying the biological effectiveness of ionising radiation can provide an important insight into ways of increasing the efficacy of radiotherapy, as well as the risks associated with exposure. This requires a multi-scale approach for modelling, not only considering the physics of the track structure from the millimetre scale down to the nanometre scale, but also the structural packing of the DNA within the nucleus, the resulting chemistry in the context of the highly reactive environment of the nucleus, together with the subsequent biological response.