Protein Oxidation Implicated as the Primary Determinant of Bacterial Radioresistance

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Abstract
In the hierarchy of cellular targets damaged by ionizing radiation (IR), classical models of radiation toxicity place DNA at the top. Yet, many prokaryotes are killed by doses of IR that cause little DNA damage. Here we have probed the nature of Mn-facilitated IR resistance in Deinococcus radiodurans, which together with other extremely IR-resistant bacteria have high intracellular Mn/Fe concentration ratios compared to IR-sensitive bacteria. For in vitro and in vivo irradiation, we demonstrate a mechanistic link between Mn(II) ions and protection of proteins from oxidative modifications that introduce carbonyl groups. Conditions that inhibited Mn accumulation or Mn redox cycling rendered D. radiodurans radiation sensitive and highly susceptible to protein oxidation. X-ray fluorescence microprobe analysis showed that Mn is globally distributed in D. radiodurans, but Fe is sequestered in a region between dividing cells. For a group of phylogenetically diverse IR-resistant and IR-sensitive wild-type bacteria, our findings support the idea that the degree of resistance is determined by the level of oxidative protein damage caused during irradiation. We present the case that protein, rather than DNA, is the principal target of the biological action of IR in sensitive bacteria, and extreme resistance in Mn-accumulating bacteria is based on protein protection. One original goal of radiobiology was to explain why cells are so sensitive to ionizing radiation (IR). Early studies in bacteria incriminated DNA as the principal radiosensitive target, an assertion that remains central to modern radiation toxicity models. More recently, the emphasis has shifted to understanding why bacteria such as Deinococcus radiodurans are extremely resistant to IR, by focusing on DNA repair systems expressed during recovery from high doses of IR. Unfortunately, as key features of DNA-centric hypotheses of extreme resistance have grown weaker, the study of alternative cellular targets has lagged far behind, mostly because of their relative biological complexity. Recent studies have shown that extreme levels of bacterial IR resistance correlate with high intracellular Mn(II) concentrations, and resistant and sensitive bacteria are equally susceptible to IR-induced DNA damage. The current work establishes a mechanistic link between Mn(II) and protection of proteins from radiation damage. In contrast to resistant bacteria, naturally sensitive bacteria are highly susceptible to IR-induced protein oxidation. We propose that sensitive bacteria sustain lethal levels of protein damage at radiation doses that elicit relatively little DNA damage, and that extreme resistance in bacteria is dependent on protein protection.