DEINOCOCCUS RADIODURANS AND ELECTRON PARAMAGNETIC RESONANCE: a ‘Rosetta stone’ in the modern decryption of radiation resistance

Functional genome studies fail to predict cell survival after ionizing radiation, leaving the perplexing problem as to how genes control radiation resistance.

In 2003, Dr. Michael Daly, Professor of Pathology, developed paradigm-altering technologies that address resistance to irradiation-induced injury (Transcriptome dynamics of Deinococcus radiodurans recovering from ionizing radiation [PNAS 2003, 100:4191]) and extended these findings in 2015 (reconstituted Mn2+-peptide complex of Deinococcus radiodurans preserves immunogenicity of lethally irradiated vaccines against viruses and Staphylococcus aureus [Cell Host Microbe 2012 12:117]). His latest major technology development “Across the Tree of Life, Radiation Resistance is Governed by Antioxidant Mn2+, Gauged by Paramagnetic Resonance” was published in the Proceedings of the National Academy of Sciences (PNAS 2017, 114:E9253) and demonstrates the universal impact of the model he calls “Death by Protein Damage in Irradiated Cells” (DNA Repair 2012, 11:12).

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His evidence shows that small antioxidant complexes of Mn2+ (H-Mn2+) are responsible for cellular radiation resistance, and that H-Mn2+ protects the proteome, not the genome from radiation-induced reactive oxygen species (ROS) (Nat Rev Microbiol 2009, 7:237). The paradigm shifted when comparative genome and whole-proteome mass spectrometry analyses of Deinococcus spp. identified that only a few genes that make significant contributions to recovery of irradiated D. radiodurans, and that these DNA repair genes do not predict radiation-resistance (Microbiol Mol Biol Rev 2001, 65:44, Stand Genomic Sci. 2017, 12:46). Rather, Daly reported that bacterial radiation resistance was strongly correlated to intracellular Mn content, which could be interrogated by electron paramagnetic resonance (EPR) spectroscopy (Science 2004, 306:1025). In 2007, Daly and DOE colleagues identified a Mn2+-dependent, non-enzymatic mechanism that confers extreme radiation resistance (PLoS Biology 2007, 5:e92).

The shift in focus from DNA to proteins in radiation survival led to the discovery that the H-Mn2+ content of non-irradiated living cells is readily gauged by advanced forms of EPR spectroscopy and are highly diagnostic of their DNA repair efficiency and survival after acute radiation exposures (PNAS 2017, 114:E9253). EPR measurement of cellular H-Mn2+ content is the strongest known discriminator of cellular radiation resistance across all 3 domains of life spanning hundreds of Gray for bacteria and yeasts, to just a few Gray separating radiation-resistant from radiation-sensitive cancer cells. Dr. Daly’s 2017 PNAS article identifies the universal impact of this model he calls “Death by Protein Damage in Irradiated Cells” (DNA Repair 2012, 11:12).

Nucleic acid-based approaches that gauge radiosensitivities of human cancer cell lines have been futile owing to the lack of distinct gene targets responsible for ionizing radiation resistance. Thus, Dr. Daly’s 2017 PNAS article gives realistic hope to personalized radiotherapy whereby the EPR could precisely determine radiosensitivity of a particular cell or even cancer cell type. The accumulation of H-Mn2+ to prevent proteome oxidation as a tactic for radiation survival received broad support among preeminent leaders in the field of DNA repair, despite rigorous experimental challenges (Kriško and Radman, Cold Spring Harb Perspect Biol 2013, 5:a012765). Thus, Daly’s article now also serves as a ‘Rosetta stone’ in the modern decryption of radiation resistance.