LINE-1 in response to exposure to ionizing radiation

Abstract

It is becoming increasingly recognized that Long Interspersed Nuclear Element, 1 (LINE-1), the most ubiquitous repetitive element in the mammalian genomes, plays an important role in the pathogenesis of disease and in the response to exposure to environmental stressors. Ionizing radiation is a known genotoxic stressor, but it is capable of targeting the cellular epigenome as well. Radiation-induced alterations in LINE-1 DNA methylation are the most frequently observed epigenetic effects of exposure. The extent of this aberrant DNA methylation, however, strongly depends on a number of factors, including the type and dose of radiation. Two other factors are being discussed in this commentary-the evolutionary age and type of the LINE-1 promoter, as well as the type of irradiated cell. This knowledge will further aid in elucidating the mechanisms of response to ionizing radiation exposure, as well in understanding the pathogenesis of the negative health effects associated with exposure. LINE-1 DNA methylation Long Interspersed Nuclear Element, 1 (LINE-1) is the most ubiquitous transposable element in the mammalian genomes, accounting for approximately 17% of the human and 20% of the mouse genomes. 1 A typical mam-malian LINE-1 element contains a 5 0-UTR, two open-reading frames-ORF1 and ORF2-and a 3 0-UTR. While both ORFs are AT-rich, the 5 0-UTR of LINE-1 elements in mammals is enriched in GC, with an average GC content of 57.2%. 2 This high density of GpC dinucleotides forms a heavily methylated CpG island in the promoter region of LINE-1. Methylation of LINE-1 DNA is considered among the primary mechanisms for its silencing and prevention of unwanted retrotransposition. 3 Exposures to various environmental stressors have been shown to affect the DNA methylation status of LINE-1. 4 Alterations in DNA methylation may result in the loss of the epigenetic control over LINE-1 and lead to its transcriptional reactivation and retrotransposition. The latter event may lead to disruptive insertional muta-genesis when LINE-1 (most frequently-its 5 0-truncated transpositionally inactive fragment) can be introduced within the ORF of the functional gene, leading to the aberrant function of the latter. LINE-1 DNA hypomethy-lation and retrotransposition have been associated with genomic instability and development of numerous pathological states, including cancer. 5 Even without retro-transposition, aberrant LINE-1 DNA methylation can substantially affect the tumor landscape. For instance, loss of DNA methylation in the intronic regions of MET, RAB3IP and CHRM3 proto-oncogenes within the fragments that owe to previous LINE-1 insertions leads to inadvertent activation of methylation-silenced genes, and is inversely correlated with metastasis-free survival and response to cancer therapy. 6,7 LINE-1 and ionizing radiation Ionizing radiation (IR) is a ubiquitous genotoxic stressor with recognized ability to alter the cellular epigenome. Exposure to IR often leads to the loss of global DNA methylation, which is attributed primarily to the loss of DNA methylation from repetitive elements and LINE-1 in particular (for a review, see ref. 8). This effect is mostly observed after exposures to doses of 1 Gy and above. At the same time, with the Comment on: Prior S, et al. Densely ionizing radiation affects DNA methylation of selective LINE-1 elements. Environ Res 2016; 150:470-81 and Miousse IR, et al. Inter-strain differences in LINE-1 DNA methylation in the mouse hematopoietic system in response to exposure to ionizing radiation. Int J Mol Sci 2017; 718(7) pii: E1430.