2017 Michael Fry Award Lecture When DNA is Actually Not a Target: Radiation Epigenetics as a Tool to Understand and Control Cellular Response to Ionizing Radiation

Abstract

Aside from the generally accepted potential to cause DNA damage, it is becoming increasingly recognized that ionizing radiation has the capability to target the cellular epigenome. Epigenetics unifies the chemical marks and molecules that collectively facilitate the proper reading of genetic material. Among the epigenetic mechanisms of regulation, methylation of DNA is known to be the key player in the postirradiation response by controlling the expression of genetic information and activity of transposable elements. Radiation-induced alterations to DNA methylation may lead to cellular epigenetic reprogramming that, in turn, can substantially compromise the genomic integrity and has been proposed as one of the mechanisms of radiation-induced carcinogenesis. DNA methylation is strongly dependent on the one-carbon metabolism. This metabolic pathway is central to the support of DNA methylation by means of providing the donor of methyl groups, as well as for the synthesis of amino acids. To better understand the mechanisms of radiation-induced health effects, we study how exposure to radiation affects DNA methylation and one-carbon metabolism. Also, a tight interaction that exists between DNA methylation and one-carbon metabolism allows us to simultaneously manipulate both cellular epigenetic and metabolic profiles to modulate the normal and cancerous tissue response to radiotherapy.

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

“…[137,268] (2) DNA hypomethylation of more recent L1 retrotransposons [137,268] (3) Over expression of DNMT3B contributing to p53 and p21 silencing by DNA methylation.…”

“…Although irradiation induces DNA damage, numerous irradiation experiments highlight epigenetic deregulation [363], effects distant from target cells, and persistent effects that can inform about carcinogenic mechanisms for consideration in the development of testing strategies for NGTxC. GGDHo and genomic instability are induced by ionizing radiation in exposed cells [364], but also in cells distant from the irradiated sites with GGDHo that still persist 7 months after exposure [137,268]. Indirect effects in unexposed cells, referred to as field or bystander effects, and persistent effects in subsequent generations of unexposed cells, all imply active mechanisms.…”

“…Koturbash [268] reported that irradiation induces changes in DNAm that are cell type and assay dependent, with assays targeting LL1 of old evolutionary age showing hypermethylation, while those of younger age showing hypomethylation. LL1 hypomethylation can lead to its activation and promote aberrant transcription, alternative splicing, insertional mutagenesis, DNA damage, and genome instability [371].…”

Long INterspersed element‐1 mobility as a sensor of environmental stresses

“…Indeed, IR has been shown to affect global DNA methylation in general and DNA methylation of L1 in particular, causing demethylation or hypermethylation, depending on doses and types of IR (Miousse et al ., ). Recently, it has been demonstrated that effects of IR on L1 DNA methylation can also depend on the type of the L1 promoter, as well as on the type of irradiated cells (Prior et al ., ; Miousse et al ., ; Koturbash, ).…”

Ionizing Radiation-Induced Epigenetic Modifications and Their Relevance to Radiation Protection

“…Their hypomethylation, especially in the regions called “Long Interspersed Nucleotide Element 1” (LINE-1), has been observed in virtually all human cancers and is frequently associated with a poor prognosis [ 70 ]. Loss of DNA methylation in the TEs enhances transcriptional activity so that reactivation of TEs potentially leads to GI [ 58 , 71 , 72 , 73 , 74 ], considered as a major hallmark of many cancer ([ 75 ] and refs therein). Many lines of evidence clearly demonstrate that alterations in methylation and expression of TEs are caused by exposure to environmental stressors, many of which are carcinogens or suspected carcinogens so that it has been proposed that TEs can serve as biomarkers of exposure to environmental stressors [ 72 ].…”