Across the tree of life, radiation resistance is governed by antioxidant Mn ²⁺ , gauged by paramagnetic resonance

Abstract

SignificanceDecades of functional genomic efforts have failed to predict the ability of cells to survive ionizing radiation (IR). Evidence is mounting that small high-symmetry antioxidant complexes of manganous ions with metabolites (H-Mn2+) are responsible for cellular IR resistance, and that H-Mn2+ protects the proteome, not the genome, from IR-induced reactive oxygen species. We show that the amount of H-Mn2+ in nonirradiated living cells is readily gauged by electron paramagnetic resonance (EPR) spectroscopy and highly diagnostic of their DNA repair efficiency and survival after gamma-radiation exposure. This spectroscopic measure of cellular H-Mn2+ content is the strongest known biological indicator of cellular IR resistance between and within organisms across the three domains of the tree of life, with potential applications including optimization of radiotherapy.

The response of the melanized yeast Exophiala dermatitidis to gamma radiation exposure

“…dermatitidis has an LD 10 of approximately 3000 Gy. In aqueous conditions, γ‐radiation generally produces DNA DSBs at a similar rate in all organisms [0.005 DSB/Gy/Mbp (Campa et al ., ; Daly, ; Sharma et al ., )] so the number of DSB that correspond to this LD 10 dose in E . dermatitidis [with a genome size of 26.5 Mbp (Chen et al ., )] is 397.5.…”

“…This has been seen before with strains of S . cerevisiae (Sharma et al ., ), Deinococcus species (Makarova et al ., ), Drosophila melanogaster (Vaisnav et al ., ) and human cell lines (Fertil and Malaise, ), and it demonstrates that IR resistance, even though it cannot be selected for in nature, can likely be achieved with relatively few mutations. If this hypothesis is correct, further characterization of strain‐specific radioresistance coupled to genome‐wide association studies hold great potential for understanding this resistance phenotype.…”

Transcriptomic analysis reveals the relationship of melanization to growth and resistance to gamma radiation in Cryptococcus neoformans

“…DNA damage proteins) to protect fungi from radiation-induced cell death, however, remains incomplete. Moreover, fungal cells without melanin have also shown resistance to high levels of IR (Holloman et al, 2007;Sharma et al, 2017;Shuryak et al, 2017).…”

Distributions of manganese in diverse human cancers provide insights into tumour radioresistance

“…The enzymatic activities of superoxide dismutase, catalase and glutathione peroxidase were minor contributors. [12][13][14][15][16][17][18][19] We pursued this metabolic area in the context of human tumours because we reasoned that the fundamental properties of Mn, with its 5 unpaired electrons in its 3d orbital, and its conserved chemistry of interactions, should apply to human cancers. We therefore undertook an analysis of patient samples from different human tumour types where clinically-inferred radioresistance had been examined (Table 1), with the aim of using LA-ICP-MS to determine if measurements of Mn levels in tumours could be helpful in the radiation treatment of cancer patients.…”

“…We deemed it likely that total Mn content in tumours would be a reasonable proxy of Mn 2+ in high symmetry complexes, which are the strongest indicator of radioresistance to date. 19 Since the other key components of Mn…”