Chromatin and the Cellular Response to Particle Radiation-Induced Oxidative and Clustered DNA Damage

Abstract

Exposure to environmental ionizing radiation is prevalent, with greatest lifetime doses typically from high Linear Energy Transfer (high-LET) alpha particles via the radioactive decay of radon gas in indoor air. Particle radiation is highly genotoxic, inducing DNA damage including oxidative base lesions and DNA double strand breaks. Due to the ionization density of high-LET radiation, the consequent damage is highly clustered wherein ≥2 distinct DNA lesions occur within 1–2 helical turns of one another. These multiply-damaged sites are difficult for eukaryotic cells to resolve either quickly or accurately, resulting in the persistence of DNA damage and/or the accumulation of mutations at a greater rate per absorbed dose, relative to lower LET radiation types. The proximity of the same and different types of DNA lesions to one another is challenging for DNA repair processes, with diverse pathways often confounding or interplaying with one another in complex ways. In this context, understanding the state of the higher order chromatin compaction and arrangements is essential, as it influences the density of damage produced by high-LET radiation and regulates the recruitment and activity of DNA repair factors. This review will summarize the latest research exploring the processes by which clustered DNA damage sites are induced, detected, and repaired in the context of chromatin.

The Effects of Particle LET and Fluence on the Complexity and Frequency of Clustered DNA Damage

“…It is well known that high-LET particles induce complex molecular damage, e.g., clustered DNA-lesions, which may have a different biological response compared to simple damage induced by low-LET radiations [ 8 , 64 , 70 , 71 ]. The characterization of the damage as a function of LET can then be the initial step in their biological quantification due to high-LET radiations.…”

Chromosomal damage, gene expression and alternative transcription in human lymphocytes exposed to mixed ionizing radiation as encountered in space

“…High- and low-LET radiations differ in the structure of the track along which energy is deposited inside a cell nucleus. Alpha particles induce a highly heterogeneous pattern of DNA damage and breaks along a narrow alpha-particle track resulting in closely spaced, correlated breaks which are more likely to mis-repair and form mutations and aberrations, possibly leading to cell death, compared to the more homogeneously and sparsely distributed breaks produced by X-rays 33 . The complexity of DNA damage increases with LET by virtue of additional strand breaks and/or base damage within a distance of few base pairs 34 .…”

Consequences of changing Canadian activity patterns since the COVID-19 pandemic include increased residential radon gas exposure for younger people

“…Those who are younger, in work, and who live in urban and suburban regions are among the most impacted, and are now experiencing significantly increased doses of radiation to their lungs from residential radon gas exposure. Based on all available information regarding radon exposure 2,[9][10][11]13,14,16,20 , this is expected to increase lifetime lung cancer risk for populations moving forward. Additionally, we note that the workers who are most impacted (i.e., those working in office/desk jobs that are now more likely to be performed from a residential property for at least part of the time) are a group that is not traditionally considered in occupational health campaigns.…”

“…Repeated, long term radon inhalation is a primary cause of lung cancer amongst people who have never smoked tobacco 2,3,5,6,[9][10][11][12][13][14][15] , a disease that is now the 7 th leading cause of cancer-linked death globally 9,[16][17][18][19] . The inhalation of radon and its progeny can increase lung cancer risk as they emit alpha particle radiation within the lungs, which damages lung epithelial cell DNA and thereby increases the risk of cancer-causing mutations 2,[20][21][22][23] . Radioactivity levels from radon in air are measured in Becquerels (Bq) per cubic meter (m 3 ), equal to one alpha particle (radioactive) emission per second per cubic metre of air 2 .…”