It was nearly 50 years ago that the American scientist Arthur W. Anderson eyed an irradiated can of ground meat and made an intriguing discovery. Growing on the meat, seemingly unaffected by the intense ionizing radiation that had killed the other microorganisms around it, was a curious red bacterium.
Follow-up studies confirmed that this organism, later named Deinoccocus radiodurans, not only was radiation resistant, it brought a whole new meaning to the term. At 1 million rads of radiation energyor 1,000 times the dose of radiation energy dropped on Hiroshima and Nagasakithe growth of D. radiodurans simply slows down. At 1.75 million rads, about 35% of the bacteria survive, and at 3 million rads, a few copies of the bacterium still cling to life.
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However, the answer may finally be coming into focus. A team of scientists, led by Yuejin Hua, Ph.D., now at Zhejiang University in China, recently reported that, when exposed to radiation, the bacterium relies on "a general switch"a protein called PprIto orchestrate its DNA repair activities. Flip this control switch, the scientists say, and multiple, still-undefined signaling pathways kick into gear to provide extreme radiation resistance.
Using PprI as their bait, Huas group and others already have begun the long process of identifying the proteins that line up along these pathways, a key first step before attempting to define the specific mechanisms that power the repair process. "Im always hesitant to say something like this, because I know how you get your fingers smashed making these statements," said John Battista, Ph.D., a scientist at Louisiana State University in Baton Rouge, who has studied D. radiodurans for the past 12 years. "But I think we might have a real good shot in the not-too-distant future of finally getting something figured out."
Cancer Model?
If, as many scientists contend, human cancer frequently involves a breakdown in DNA repair, what might a well-characterized D. radiodurans mean for cancer research? According to several basic researchers, the answer depends on ones brand of science.
From the dominant, "all-is-mechanism" perspective of the molecular biologist, D. radiodurans likely has little to offer in helping to directly define the biocircuitry that powers the human DNA repair system. This soil-dwelling prokaryote is unicellular, nonmotile, and contains four to 10 duplicate copies of its genome. Moreover, of its proposed 3,187 genes, more than half are of unknown function and roughly 1,000 are totally unique, suggesting that humans and D. radiodurans have little directly in common biochemically.
But, from the increasingly influential perspective of comparative genomicsthe study of DNA structure and its evolution across speciesa well-characterized D. radiodurans could provide another important model to help define the basic biochemical principles underpinning DNA repair in all organisms. These include the evolution of various DNA repair pathways involved in excision repair, mismatch repair, and recombinational repair, all of which have direct application to cancer.
"My view is that, while E. coli and some other model systems, like yeast, have given us important insights into the basic processes of repair, it may push out the envelope to learn some lessons from the exceedingly radioresistant organisms," said Philip Hanawalt, Ph.D., a longtime leader in the field of DNA repair and a scientist at Stanford University in Palo Alto, Calif. "This is true especially as we enter the era of potential gene therapy. Comparative studies on DNA repair in a variety of model organisms may give us some important clues as to what is universally important as well as how the evolution of DNA repair has occurred to bring us humans to the present state."
Some also speculate that D. radiodurans could be a valuable research tool to advance radiation oncology. Binghui Shen, Ph.D., a scientist at the Beckman Research Institute in Duarte, Calif., said that the goal would be to identify all of the molecules and mechanisms induced by radiation treatment in humans and bacteria, then look for parallels in mechanistic responses.
"D. radiodurans is a simple organism," said Shen. "We could rapidly get a lot of information on the functional mechanisms of radioresistance. Then, we can apply this knowledge for clues to why human tumors sometimes become resistant to radiation therapy."
New Clues
The recently published paper on the PprI protein is an example of just how intriguing, but complex, these clues are likely to be. Hua and colleagues determined that PprI is not related to any known protein in various organisms, from human to archaea. This would suggest that the protein is a biologic anomaly that is a weird story unto itself.
But, in actuality, proteins exist as many stories within a story because of the various amino-acid motifs and active sites stitched into their overall structure. Such is also the case with PprI. According to Hua, he and his colleagues have identified two known sequence motifsa zinc-binding signature and a lacI family signaturethat are typically found in proteins that regulate gene expression, and several potential phosphorylation sites. Hua said his group already has begun to analyze the crystal structure of PprI in hopes of better determining its relationship between form and function.
Shen, also an author on the paper, warned that to dismiss PprI as irrelevant to human biology based on sequence structure alone might be a case of jumping the gun. After all, the most meaningful biologic information is not DNA structure, it is protein structure. "If you look at the DNA sequence encoding this protein, it may not be so conserved in nature," said Shen. "But when you look at the translated, three-dimensional structure and the functional implications of this protein, I think those functional mechanisms may exist in people."
According to Battista, whose group last year published the first description of this protein, which it named IrrE, Huas work also raises another intriguing, but complex, point about the evolution of DNA repair. He said the group showed that, in D. radiodurans, PprI regulates the activity of the RecA protein, a critical enzyme in controlling the DNA repair process in E. colinot the other way around, as most scientists would expect. "Thats very exciting because it implies that there are other things floating around out there that may be important and perhaps as important as RecA," said Battista. "Its also somewhat revolutionary, since everybody just assumed that its RecA that does everything in Deinococcus radiodurans."
It also further implies that, as DNA repair evolved, its pathways zigged in some organisms, zagged in others, and proceeded along alternate routes in still others. "As you get into other bacteria, you start finding that not all of them do things the same way," said Michael Cox, Ph.D., a scientist at the University of Wisconsin in Madison. "For instance, Deinococcus radiodurans lacks the major repair pathway for double strand breaks that exists in E. coli. So, clearly, its doing something differently."
Funding Agency Interest
About a dozen laboratories around the world now study D. radiodurans. Of the handful of laboratories in the United States, most receive their research funding from the Department of Energy, which is interested in the bacteriums potential to clean up toxic waste in high-radiation environments. Also interested in D. radiodurans are NASA, the National Science Foundation, and the Department of Defense.
The National Institutes of Health has largely been absent from the game. NIH currently supports five grants involving D. radiodurans, in most cases only peripherally, and none deal specifically with cancer. At issue has been how this distantly related organism could possibly benefit human health, NIHs primary research mission.
"NIH has always thrown the thing back at us, in that they think it is too esoteric," said Battista. "Its exotica, I think is the term. But, if tomorrow we found something that just sealed up double strand breaks like nobodys business, and we thought that we could put it in mammalian cells, I think wed get funded in a heartbeat. I guess from that point of view, the onus has been put on us."
That onus will likely grow less daunting in the coming months. Hua said he and his collaborators have some interesting data in press, and Battista and colleagues have generated a great deal of information to begin defining in greater detail the pathways in D. radiodurans that are operative during the DNA repair process.
"When I go and talk about Deinoccocus, people are just amazed at what it can do," said Battista. "Their imaginations just run wild. Were going to push real hard in the next year to start making some headway, and, hopefully, somebody will solve it before I retire or pass away. Well see how it goes."
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