Hardy Bacterium's DNA Repair Process Shows Way to Immortality

Thursday, September 28, 2006

By Ker Than

Scientists have discovered a novel genetic repair process that allows a hardy desert microbe to die and resurrect itself over and over again.

The finding, detailed in the Sept. 28 issue of the journal Nature, could lead to new forms of regenerative medicines and might even allow scientists to one day bring dead cells in our own bodies back to life. Deinococcus radiodurans is a so-called extremophile bacterium that can survive intense bouts of heat and ultraviolet radiation, the latter of which shatters its genome into hundreds of DNA fragments.

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Without a genome, the microbe is effectively dead because it can't synthesize the proteins necessary for life. In only a few hours, though, Deinococcus can reassemble its genome and return to life. "This is the first case, I think, of a living cell that clinically dies  its DNA is chopped into little pieces and it has no metabolism  when desiccated, and yet, as long as it can reconstitute its genome, it reconstitutes its own life," said study team member Miroslav Radman of the University of Paris. The microbe is able to perform its remarkable feat because, like other bacteria, it carries at least two, sometimes more, copies of its genome and also because radiation damages DNA randomly. So even if both genome copies are damaged, they likely aren't damaged in the same spots.

With the right tools, a microbe can piece together what the original sequence was.

Returning to life

Here's how it works: When it Deinococcus' genome initially shatters, it breaks apart into numerous double-stranded DNA fragments. Proteins chew away at the ends of the fragments, creating overhanging single-stranded DNA "tails." The tails are called "sticky-ends" because they can combine with each other.

To function, the sticky-ends have to contain complementary DNA sequences. DNA is made up of four amino-acid bases, or "letters," that combine in specific ways: adenine (A) always pairs with thymine (T) and guanine (G) with cytosine (C). So if the sequence on one tail is ATG, it can pair with another tail whose sequence is TAC. Two complimentary sticky ends will fit together naturally like toy Lego blocks. The sticky-ends allow sequential DNA fragments to be joined together to form linear, double-stranded intermediate pieces. A protein then arranges the double-stranded pieces into circular chromosomes, which are characteristic of bacteria. "Once the genome is reconstituted, the cell can synthesize [again] all of its proteins, lipids and membranes and the cell resurrects," Radman said.

Potential human applications

Although the basic mechanism behind Deinococcus' hardiness is understood, many mysteries still remain. For one, proteins are needed for DNA repair and synthesis, but proteins can be damaged by radiation, too. It's one thing to piece together a broken genome, but how does Deinococcus do it with broken tools? "That's still a mystery," Radman told LiveScience. "How, after months of desiccation and burning from UV sunlight in the desert, is there still sufficient protein activity to start reconstituting DNA? We don't know." One possibility is that Deinococcus' proteins are resistant to dehydration, in the same way proteins in thermophilic bacteria are resistant to temperature. Radman believes his team's findings open up the possibility of resurrecting dead cells in our own bodies, specifically those in our brains. "It allows us now, legitimately, to dream of bringing back to life dead, or close-to-dead, neurons," he said.

Unique strategy

Unlike most bacteria studied in biology, such as E. coli and salmonella, Deinococcus is a slow grower. It didn't evolve to divide rapidly, but to be robust.

"It sort of went the other way of capitalism  it doesn't care about growth and fast division because it doesn't need to compete in the desert with anybody," Radman said. "So in that sense, Deinococcus is the bacterial paradigm of neurons, which [usually] don't divide during our lifetimes." Like Deinococcus, neurons carry two  albeit slightly different  copies of their genomes: one from Mom and the other from Dad. In fact, all the cells in our bodies, except sperm and eggs, contain two genome copies. Therefore, it's possible that one day scientists could resurrect dead neurons using repair mechanisms similar to those employed by Deinococcus, Radman said.

 

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Updated: 12:49 p.m. ET Oct. 3, 2006

ZAGREB, Croatia - Scientists have worked out how a radiation-resistant bacterium that can exist in extreme conditions repairs damage to itself, a discovery which could provide clues about diseases such as cancer. The organism called Deinococcus radiodurans is so hardy it can survive ionizing radiation 5,000 times stronger than the level lethal to humans. "Through evolution, the bacteria have developed a mechanism to precisely reconstruct its DNA. Until now this has been a scientific riddle," Ksenija Zahradka, a leading researcher in the study, told a news conference. "It is an extremely fascinating phenomenon to see how a cell itself can repair its fairly destroyed DNA. We will use this knowledge to try to find ways how cells that are not so resistant could do the same."

The scientists, whose findings were reported last week online by the journal Nature, described the two-stage method in which the bacterium rebuilds its genome. Many diseases, including cancer, involve alterations to DNA and an inability to recover from the damage. "Therefore, any understanding of self-repair mechanisms could help in that regard. Now we'll focus to see if there are other organisms which can do the same," Zahradka said. Cosmic Log: Lord of the DNA ring The study was completed in cooperation between the Croatian research institute Rudjer Boskovic and the Paris-based Necker Institute, where Croatian scientist Miroslav Radman supervised the experimental part of the study. Deinococcus radiodurans, a scientific name that is taken from Latin for "strange berry that withstands radiation," was discovered 50 years ago in a can of spoiled meat. It can survive in deserts or on other surfaces exposed to strong heat where all other organisms perish because of dehydration and ultraviolet rays that shatter the cellular DNA into fragments.