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

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 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.

Keywords:

• DNA methylation
• mitochondria
• ionizing radiation
• genomic instability
• oxidative stress

Acknowledgments

The author would like to thank Drs. Charles Limoli and Munjal Acharya for stimulating discussions regarding this manuscript. This manuscript touches on a number of fields of research and large bodies of literature. As such, the author would like to apologize for not being able to reference every publication salient to the discussion. Lastly, the author would like to acknoweldge Dr. William F. Morgan, not just because he was an integral contributor to that long ago first draft, but also to remember his wit, irreverance and unflagging friendship that he generously shared with so many of us.

Disclosure statement

The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.

Additional information

Funding

This work was supported by Defense Threat Reduction Agency grant HDTRA 1-16-1-0022 and NASA grant NNX15AI22G to JEB.

Notes on contributors

Janet E. Baulch

Janet E. Baulch, Ph.D. is a Project Scientist in the Department of Radiation Oncology at UC Irvine. Over the years she has worked to understand the role of epigenetic mechanisms in the radiation response.