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

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Abstract
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 epigentic 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 perpeturate 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. I began writing this paper in 2011 as a team effort with my mentor, colleague and good friend Bill Morgan when he was invited to write a prospect paper under the working title of ‘Epigenetic Parameters of Radiation Induced Genomic Instability’. One of us would write a bit and then send it to the other, who would inevitably be chasing some other project or deadline. The manuscript would then languish for a time until one of us picked it up again for another go at it. I can still hear Bill’s voice over the phone in subsequent years saying to me, ‘Hey JEB, that manuscript was really good! How come we never finished it?’ I now find myself wondering the same thing. Clearly it is not the same paper that it would have been with the benefit of Bill’s contribution and while the concepts, discoveries and details defining radiation effects and epigenetics have since changed, I hope this manuscript captures the essence of what we began pondering some years ago.
Funding Information
  • Defense Threat Reduction Agency (HDTRA 1-16-1-0022)
  • Defense Threat Reduction Agency (NNX15AI22G)

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