23rd Annual NASA Space Radiation Investigators' Workshop (2012)
8092.pdf
Epigenetic and Genomic Alterations in Radiation Induced Genomic Instability
Dacheng Ding1, Stefani N. Thomas1,2, Umut Aypar3, Wilfried Goetz1, Katrina M.
Waters4, William F. Morgan4, Austin J. Yang2,5, Janet E. Baulch1
1
Department of Radiation Oncology, Radiation Oncology Research Laboratory,
University of Maryland School of Medicine, Baltimore, MD
2
The Greenebaum Cancer Center, University of Maryland, Baltimore, MD
3
Mayo Clinic, Rochester, MN
4
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA
5
Department of Anatomy and Neurobiology, University of Maryland, Baltimore, MD
Radiation induced genomic instability is a well-studied phenomenon that is measured as
mitotically heritable genetic alterations observed in the progeny of an irradiated cell.
However, radiation induced mutations alone cannot account for the unstable phenotype.
While the mechanisms that perpetuate this instability remain unclear, epigenetic
mechanisms have frequently been implicated and a role for chronic oxidative stress and
mitochondrial dysfunction has consistently been demonstrated.
We tested the
hypothesis that epigenetic mechanisms contribute to the perpetuation of the unstable
phenotype by evaluating global, repeat element and specific locus DNA methylation, as
well as by evaluating microRNA (miR) expression. In order to clarify the role of
mitochondrial dysfunction in genomic instability, we also evaluated the mitochondrial
sub-proteome. In this study, changes in global and repeat element DNA methylation
were found to be associated with the instability phenotype, but no changes in promoter
DNA methylation were observed for the loci evaluated. Analysis of miR identified miR
for which anti-correlated gene expression or mitochondrial protein levels was observed.
Proteomic analysis demonstrated significantly reduced levels electron transport chain
proteins and increased levels of tricarboxylic acid cycle enzymes and proteins that
protect against oxidative stress and apoptosis. Together, these data demonstrate that
more than one cellular defect contributes to the genomic instability phenotype and that
epigenetics is likely to play a role in the phenotype. These data also suggest that
unstable cells adapt mechanisms that allow survival under sub-optimal conditions to
perpetuate genomic instability.
[This work supported by NASA grants NNX07AT42G, NNJ06HD31G and DOE grant
DE-FG02-07ER64339].