Epigenetic Alterations in Radiation-Induced Genomic Instability

Abstract

Radiation can lead to carcinogenesis through targeted and non-targeted effects. One non-targeted effect, radiation-induced genomic instability (RIGI), results in an increased frequency of genetic alterations in the progeny of irradiated cells. RIGI is thought to be an early event in radiation-induced carcinogenesis, but it is unknown how this process is initiated. Epigenetic changes, including aberrant DNA methylation and altered microRNA (miRNA) expression, can be induced by radiation exposure and have been associated with some cancers. We are testing the hypothesis that irradiation results in epigenetic alterations that are involved in the initiation and perpetuation of RIGI. The human-Chinese hamster ovary hybrid cell line GM10115 was irradiated using x-rays or iron (Fe) ions and clones were obtained. Irradiation induced DNA damage in GM10115 cells and RIGI in clones (114, 118, CS9, LS12, 115, Fe5.0-8) was determined using micronucleus formation and fluorescence in situ hybridization analysis of chromosomal rearrangements. To study epigenetic changes, the post-irradiation status of specific locus, repeat element, genome-wide methylation, and miRNA profiles were evaluated. Results suggest that aberrant DNA methylation changes in miRNA expression are induced by irradiation. In the unstable clones, results suggest that changes in DNA methylation and aberrant expression of miRNA can be associated with RIGI. Thus, epigenetic changes in chromosomally unstable clones could suggest that epigenetic aberrations may be perpetuating RIGI.