The Cellular Response to Complex DNA Damage Induced by Ionising Radiation

Beth Wilkinson, Mark A Hill, Jason L Parsons*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

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Abstract

Radiotherapy (ionising radiation; IR) is utilised in the treatment of ~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.

Original languageEnglish
Article number4920
Number of pages15
JournalInternational Journal of Molecular Sciences
Volume24
Issue number5
DOIs
Publication statusPublished - 3 Mar 2023

Bibliographical note

Funding:
This research was funded by the Medical Research Council (MRC), grant number MR/V028944/1; and by the National Institutes of Health (NIH), grant number R01CA256854.

Keywords

  • Humans
  • DNA Damage
  • DNA Repair
  • Radiation, Ionizing
  • DNA Repair Enzymes/genetics
  • DNA

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