The Cellular Response to Complex DNA Damage Induced by Ionising Radiation

Radiotherapy (ionising radiation; IR) is utilised in the treatment of similar to 50% of all human cancers, and where the therapeutic effect is largely achieved through DNA damage induction. In particular, complex DNA damage (CDD) containing two or more lesions within one to two helical turns of the DNA is a signature of IR and contributes significantly to the cell killing effects due to the difficult nature of its repair by the cellular DNA repair machinery. The levels and complexity of CDD increase with increasing ionisation density (linear energy transfer, LET) of the IR, such that photon (X-ray) radiotherapy is deemed low-LET whereas some particle ions (such as carbon ions) are high-LET radiotherapy. Despite this knowledge, there are challenges in the detection and quantitative measurement of IR-induced CDD in cells and tissues. Furthermore, there are biological uncertainties with the specific DNA repair proteins and pathways, including components of DNA single and double strand break mechanisms, that are engaged in CDD repair, which very much depends on the radiation type and associated LET. However, there are promising signs that advancements are being made in these areas and which will enhance our understanding of the cellular response to CDD induced by IR. There is also evidence that targeting CDD repair, particularly through inhibitors against selected DNA repair enzymes, can exacerbate the impact of higher LET, which could be explored further in a translational context.

Automated summary

Radiotherapy using ionising radiation is a common treatment for many cancers, as it damages the DNA of cancer cells. Complex DNA damage (CDD), which is difficult to repair, is a key contributor to the cell-killing effects of radiotherapy. The level and complexity of CDD increase with higher ionisation density of the radiation. Detecting and measuring IR-induced CDD in cells and tissues poses challenges, and there are uncertainties regarding the specific DNA repair mechanisms involved. However, advancements are being made in these areas to improve understanding of cellular responses to CDD and explore targeted therapies.