Bacteria use ‘crazy molecular mechanism’ to fight viruses. Made-to-order gene could be so toxic that cells only assemble it in emergencies
Some bacteria defend themselves against phages, viruses that look like microscopic spacecraft (pictured), by assembling a gene not in their normal genome.Eye of Science/Science Source
Bacteria use ‘crazy molecular mechanism’ to fight viruses
Made-to-order gene could be so toxic that cells only assemble it in emergencies
29 Aug 20242:00 PM ETByMitch Leslie
T-bacteriophages on E.coli
Some bacteria defend themselves against phages, viruses that look like microscopic spacecraft (pictured), by assembling a gene not in their normal genome.Eye of Science/Science Source
Viruses plague bacteria as well as people, and some bacteria deploy what one scientist calls a “crazy molecular mechanism” to defend themselves, two studies published in Science this month reveal. The bacteria conjure up an entirely new gene that isn’t normally in their repertoire. This gene, dubbed neo by both groups that unearthed it, then spawns a protein that stymies the viral invaders.
Although the mechanism seems bizarre, “these are excellent papers,” says microbiologist Aude Bernheim of the Pasteur Institute, who wasn’t connected to the research. “Both have very convincing evidence.” The findings offer the latest challenge to the misperception that genetic information flows only one way—from DNA to RNA to proteins—and raise the possibility that similar cryptic genes lurk in other organisms, even humans.
To assemble their new gene, the studies show, the bacteria exploit enzymes called reverse transcriptases, which invert a key cellular mechanism. Cells usually start with information encoded in a gene’s DNA to make RNA molecules, such as the messenger RNAs (mRNAs) that carry the instructions for synthesizing a protein. But reverse transcriptases can flip the process around and produce DNA versions of RNA molecules. Discovered in tumor-causing viruses, the enzymes also allow HIV to commandeer human cells. However, many bacteria also make reverse transcriptases, and the new work reveals how at least one kind of bacterium uses them to turn the tables on the viruses known as phages.
The two groups of researchers that uncovered this twist were independently trying to understand a mysterious antiphage defense mechanism identified in certain bacteria in 2020 by molecular biologist Feng Zhang of the Massachusetts Institute of Technology, who helped pioneer the CRISPR gene editor, and colleagues. The bacterial DNA encoding this protective system includes a sequence for a short RNA molecule that didn’t appear to be translated into a protein. It also contained the gene for reverse transcriptase. The mystery was “how could an enzyme that makes DNA be responsible for phage defense?” says Stephen Tang, an M.D./Ph.D. student at Columbia University.
Tang, along with his adviser Samuel Sternberg, headed one of the research groups that has now solved that puzzle; Zhang and his postdoctoral researcher Max Wilkinson led the second team. Each group transferred DNA encoding the protective system from an intestinal bacterium to the lab stalwart Escherichia coli, a bacterium that is easier to manipulate. They found that E. coli cells used the reverse transcriptase to fashion neo—a DNA copy of the puzzling short RNA segment—when attacked by phages. But the DNA was strange, usually containing numerous copies of the same sequence—sometimes more than 100—strung together. Reverse transcriptase normally drops off an RNA strand after it has finished making a DNA copy, but in the engineered E. coli, the enzyme apparently returned to the beginning of the strand again and again, as if playing a song on repeat.
“I was scratching my head for a long time” about the repetition, Wilkinson says. The likely explanation lies in how cells read a gene’s DNA to make a protein. To produce the needed mRNA, a cluster of proteins must first land on a DNA region called a promoter that is near the gene. In neo, each repeated segment contains two fragments of a promoter, but they are at opposite ends of the segment. By linking repeats end to end in a continuous piece of DNA, the bacteria assemble a working promoter from two separated pieces, Wilkinson, Zhang, and colleagues report online today in Science.
That promoter and the adjacent DNA newly made from the RNA can then function as a typical protein-coding gene. Made only when the bacteria are under attack, the protein forces the cells into dormancy, which blocks phages from reproducing inside them, Tang and colleagues revealed on 9 August in Science. “If the host shuts down, the virus has no resources to be able to replicate itself,” Tang says.
Why cells turn to this convoluted system, rather than churning out the antiviral protein all the time, remains unclear. One possibility is that neo’s protein is so potent it would shut down even healthy cells, so bacteria activate it only during a crisis. Alternatively, the mechanism could thwart one of phages’ infection tactics, Wilkinson says. When the viruses infiltrate a bacterium, they usually chop up its DNA. But if the bacterium can use the already existing reverse transcriptase and promoter-encoding RNA to make a new antiviral gene, it can still fight back. “It’s kind of outsmarting the virus,” he says.
The papers “make a good case and complement each other,” says molecular evolutionary geneticist Irina Arkhipova of the Marine Biological Laboratory. This do-it-yourself gene-building system “hasn’t been demonstrated in nature before, and it may open the way for potential applications.” For instance, genome engineers might be able to use the mechanism to induce cells to make new proteins.
About 5% of bacteria carry the DNA for the defensive system, and Bernheim says it might be even more widespread. “If bacteria somehow manage it, maybe other organisms also manage it.” Tang says he and his colleagues are even looking for a similar system in human cells.
doi: 10.1126/science.z6epmqm
Mitch Leslie
Mitch Leslie writes about cell biology and immunology.
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