Effects of ionizing radiation on DNA methylation: from experimental biology to clinical applications

Abstract

Purpose: Ionizing radiation (IR) is a ubiquitous environmental stressor with genotoxic and epigenotoxic capabilities. Terrestrial IR, predominantly a low-linear energy transfer (LET) radiation, is being widely utilized in medicine, as well as in multiple industrial applications. Additionally, an interest in understanding the effects of high-LET irradiation is emerging due to the potential of exposure during space missions and the growing utilization of high-LET radiation in medicine.

Conclusions: In this review, we summarize the current knowledge of the effects of IR on DNA methylation, a key epigenetic mechanism regulating the expression of genetic information. We discuss global, repetitive elements and gene-specific DNA methylation in light of exposure to high and low doses of high- or low-LET IR, fractionated IR exposure, and bystander effects. Finally, we describe the mechanisms of IR-induced alterations to DNA methylation and discuss ways in which that understanding can be applied clinically, including utilization of DNA methylation as a predictor of response to radiotherapy and in the manipulation of DNA methylation patterns for tumor radiosensitization.

Keywords: DNA methylation; Epigenetics; ionizing radiation; radiotherapy; space radiation; transposable elements.

Figure 1

Schematic representation of the LINE-1 element. Mammalian LINE-1 elements is comprised of the heavily methylated 5′-Untranslated Region (5′-UTR), less rich on CpG sites two open reading frames ORF1 and ORF2, and a 3′-UTR that ends with a Poly-A tale.

Figure 2

Alterations in the methionine cycle as a mechanism of ionizing radiation-induced DNA hypomethylation. (A) Under normal conditions, methionine (MET) is being converted into S-adenosylmethionine (SAM) by the methionine adenosyl transferase 2A (MAT2A). SAM donates its methyl group (CH₃), which is further used by the DNA methyltransferase DNMT-1 (DNMT) for post-replicative maintenance of DNA methylation. (B) Ionizing radiation may affect synthesis of methionine and/or inhibit methionine biotransformation to SAM, thus exhausting the internal resources for donors of methyl groups, resulting in hemimethylated DNA after replication.