DEFINED BIOLOGICAL MODELS of HIGH-LET RADIATION LESIONS

George Iliakis, Veronika Mladenova, Mortoga Sharif, Shipra Chaudhary, Ifigeneia V. Mavragani, Aashish Soni, Janapriya Saha, Agnes Schipler, Emil Mladenov

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

DNA double-strand break (DSB) complexity is invoked to explain the increased efficacy of high-linear energy transfer (LET) radiation. Complexity is usually defined as presence of additional lesions in the immediate proximity of the DSB. DSB-clusters represent a different level of complexity that can jeopardize processing by destabilizing chromatin in the vicinity of the cluster. DSB-clusters are generated after exposure of cells to ionizing radiation (IR), particularly high-LET radiation, and have been considered as particularly consequential in several mathematical models of IR action. Yet, experimental demonstration of their relevance to the adverse IR effects, as well as information on the mechanisms underpinning their severity as DNA lesions is lacking. We addressed this void by developing cell lines with especially designed, multiply integrated constructs modeling defined combinations of DSB-clusters through appropriately engineered I-SceI meganuclease recognition sites. Using this model system, we demonstrate efficient activation of the DNA damage response, as well as a markedly increased potential of DSB-clusters, as compared to single-DSBs, to kill cells, and cause Parp1- dependent chromosomal translocations. We propose that DSB repair relying on first line DSB-processing pathways (canonical non-homologous end joining and to some degree homologous recombination repair) is compromised within DSB clusters, presumably through the associated chromatin destabilization, leaving alternative end joining as last option and translocation formation as a natural consequence. Our observations offer a mechanistic explanation for the increased efficacy of high-LET radiation.

Original languageEnglish (US)
Pages (from-to)60-68
Number of pages9
JournalRadiation protection dosimetry
Volume183
Issue number1-2
DOIs
StatePublished - May 1 2019

ASJC Scopus subject areas

  • Radiation
  • Radiological and Ultrasound Technology
  • Radiology Nuclear Medicine and imaging
  • Public Health, Environmental and Occupational Health

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