Fundamental molecular mechanisms of low dose radiation effects and adaptive responses

点击翻译按钮获取中文摘要

My program is devoted to fundamental studies on biological effects of low dose radiation, radio-adaptation and their relationship to epigenetics and genome stability. It will address a fundamentally important issues: (i) are small doses of environmental radiation dangerous for living organisms, (ii) can organisms adapt to protracted radiation exposure, (iii) what are the mechanisms of radiation adaptive responses? I propose a new epigenetic theory of low dose radiation effects and adaptive responses whereby the mechanisms that underlie these effects are epigenetically regulated. Epigenetic alterations comprise mitotically and meiotically heritable changes in gene expression that are not caused by changes in the primary DNA sequence and include DNA methylation, histone modifications and small RNA-mediated effects. During the tenure of my NSERC program we analyzed epigenetic responses observed in higher levels of biological organization when organisms are exposed to ionizing radiation (IR). We proved that IR exposures lead to profound alterations in the epigenetic profile, and have shown that IR exposure leads to significant alterations in global DNA methylation, locus-specific DNA methylation and histone methylation. We have also shown that IR-induced epigenetic changes are linked to IR-induced genome instability and genome rearrangements in mammalian cells. Our earlier studies have provided some of the first evidence as to epigenetic underpinnings of an adaptive response to IR. Nevertheless, understanding the low dose radiation-induced epigenetic responses is a critical but currently under-investigated area of research that is crucial for furthering our fundamental understanding of how organisms deal with protracted radiation exposure and adapt to it, and for the development of appropriate exposure biomarkers and countermeasures. Hypotheses: We hypothesize that changes in DNA methylation and hydroxymenthylation and regulatory small RNAs are associated with low dose radiation-induced genome instability and adaptive responses. We predict that epigenetic changes may influence levels of genetic rearrangements (DNA recombination). The main long-term goal of this research is to dissect the molecular epigenetic basis of induction of IR-induced genome instability and adaptive responses and identify the specific and fundamental roles of epigenetic changes (i.e. DNA methylation, hydroxymethylation and small RNAs) in LDR responses and adaptive effects. Significance: Understanding the molecular changes that occur in exposed cells and organisms may assist in the development of measures to prevent deleterious effects of low dose radiation exposure on organisms and populations. We will provide important mechanistic knowledge of the adaptation to low dose radiation.