Radiation-induced genomic instability, epigenetic mechanisms and the mitochondria: a dysfunctional menage a trois?

Purpose: This article presents a perspective examining the evidence for a link between radiation-induced genomic instability, epigenetic mechanisms and mitochondrial dysfunction. Significant evidence suggests that mitochondrial dysfunction accompanies radiation-induced genomic instability. Similarly, it is well recognized that mitochondria synthesize the methyl, acetyl and phosphate donors necessary for covalent DNA and histone modifications. Although we have long invoked epigenetic mechanisms as drivers of persistent genomic instability, most studies arguably provide only correlative data to support this assertion. Conclusions: In many ways clarifying the precise mechanisms by which mitochondrial dysfunction contributes to an altered epigenetic landscape to perpetuate radiation-induced instability is still an emerging field despite the fact that we have posited exactly such for decades. This important concept has broad implications in the context of normal tissue and tumor radiation responses. A solid foundation has been laid, though, offering hints for future well-designed studies to cement the paradigm shift.