Radiation-induced genomic instability: Are epigenetic mechanisms the missing link?

Abstract

In addition to the extensively studied targeted effects of radiation, it is now apparent that non-targeted delayed effects such as RIGI are also important post-irradiation outcomes. In RIGI, unirradiated progeny cells display phenotypic changes at delayed times after radiation of the parental cell. RIGI is thought to be important in the process of carcinogenesis; however, the mechanism by which this occurs remains to be elucidated. In the genomically unstable clones developed by Morgan and colleagues, radiation-induced mutations, double-strand breaks, or changes in messenger RNA (mRNA) levels alone could not account for the initiation or perpetuation of RIGI. Since changes in the DNA sequence could not fully explain the mechanism of RIGI, inherited epigenetic changes may be involved. Epigenetics are known to play an important role in many cellular processes and epigenetic aberrations can lead to carcinogenesis. Recent studies in the field of radiation biology suggest that the changes in methylation patterns may be involved in RIGI. Together these clues have led us to hypothesise that epigenetics may be the missing link in understanding the mechanism behind RIGI.

Extreme anti-oxidant protection against ionizing radiation in bdelloid rotifers

“…The situation also arises in bacteria where, as mentioned above, the degree of IRinduced protein carbonylation bears the same quantitative relation to survival in both D. radiodurans and E. coli (11), raising the question of whether bacteria have such checkpoints (21). In some cases, however, IR-induced delayed reproductive death may depend on heritable effects not requiring DNA breakage (22). Effects that have been proposed in this regard include altered gene expression resulting from aberrant DNA cytosine methylation (23), centrosome amplification leading to multipolar mitosis (24), and self-sustaining production of hydrogen peroxide and elevated oxidative stress associated with mitochondrial dysfunction (25).…”

Radioresistance in a human laryngeal squamous cell carcinoma cell line is associated with DNA methylation changes and topoisomerase II α

“…1 One of the best-studied epigenetic phenomena is the methylation of cytosine residues located within CpG dinucleotides. [2][3][4][5] Three DNA methyltransferases (DNMTs; DNMT1, DNMT3a and DNMT3b) can add methyl groups to the 5' cytosine of a CpG dinucleotide, 6 aberrant DNA methylation is found in 2 distinct forms: hypermethylation and hypomethylation.…”

“…Furthermore, post-irradiation changes in DNA methylation have been suggested to correlate with the initiation of radioresistance. 1 Laryngeal cancer is generally treated by radiotherapy in conjunction with surgery and/or chemotherapy, 4 but tumor cells can acquire radioresistance during clinical radiotherapy based on fractionated radiation treatment. 13,14 However, while we have a partial understanding of the mechanisms underlying cellular radioresistance, the molecular events and markers underlying the acquired radioresistance of laryngeal cancer remain to be clarified.…”

X-Ray Induced Mutation Frequency at the <i>Hypoxanthine Phosphoribosyltransferase</i> Locus in Clinically Relevant Radioresistant Cells

“…In the present study, approximately 80% of the mutations that occurred in HepG2-8960-R without irradiation were point mutations ( Figure 2). Point mutations are difficult to identify with comparative genomic hybridization and are the predominant type of mutation resulting from genomic instability [20]. These findings strongly suggest that the undetected genomic instability in HepG2-8960-R resulted in a high baseline mutation frequency.…”

“…However, these studies focused on the rejoining kinetics of DNA dsbs but not the fidelity of DNA repair in radioresistant cells. Previous studies have demonstrated that genomic instability is usually observed in cells after irradiation [20] [21].…”