Biologists Patricia Foster and Jill Layton found that as E. coli cells begin to starve, the bacteria quadruple their expression of DNA Polymerase IV (Pol IV), a mutation-causing enzyme that is notoriously bad at copying DNA accurately. The culprit, the scientists discovered, is sigma-38, a stress protein that appears to activate expression of the Pol IV gene.

"We've known that bacteria respond to different kinds of stress by activating 30 genes or so," said Foster, who led the study. "We now know Pol IV is part of the response to starvation, which E. coli experience regularly during their life cycles. This polymerase may provide the bacterium with new properties that help them get out of difficulty by, for example, giving them the ability to use other food sources for growth."

The identification of genes controlling increased mutation rates in other, more dangerous bacteria could arm hospitals with a new type of weapon that helps them keep up with nosocomial infections caused by quickly mutating bacteria.

But the discovery also feeds a fiery theoretical debate over when and why a bacterium might increase its mutation rate. Many scientists contend that dramatically increased rates of mutation are almost always bad for bacteria, while others believe the bacteria depend on adaptive mutation to outlast the trials of harsh environments. Previously, the increased expression of Pol IV was thought to be limited to weird, drastic circumstances, the kind which might force a bacterium to mutate or die. But Foster and Layton have shown that a very common situation in nature -- one in which bacteria use up available food -- is enough to cause bacteria to activate Pol IV's gene, which in turn leads to increased mutations.

"In many instances where a more accurate polymerase might work, this one could now be substituted, so more mutations will occur," Foster said. "This results in more genetic variation and more properties on which natural selection might act."

DNA mutations are usually bad for bacteria, since altered genes rarely work properly. But sometimes mutations give rise to genes with new functions, endowing offspring bacteria with new properties, such as resistance to antibiotics.

Whenever bacteria reproduce, they divide in two and must make a copy of everything inside them, including their chromosomes. E. coli's DNA polymerases are replication enzymes responsible for making copies of the bacterium's DNA. Among the bacterium's suite of different DNA polymerases, Pol I, Pol II, and Pol III are extremely accurate, making exact duplicates, or near-exact duplicates, of the DNA they copy. Pol IV and Pol V, however, are remarkably error-prone, mutating the copied chromosome so that it differs in sequence from the original chromosome. Pol IV and Pol V are also known to be the only DNA polymerases that can get past DNA lesions, such as DNA damage ccaused by a traumatic chemical event inside the cell.

Foster and Layton studied the Pol IV expression patterns of 24 experimental strains of E. coli. Some strains had a functional Pol IV, and some didn't. Some strains had a functional form of the stress protein sigma-38, and some didn't. Cellular levels of sigma-38 increase during stationary phase, a slow-growth behavior caused by starvation. Under starvation conditions, the researchers found that Pol IV expression is increased from basal levels, about 250 copies of Pol IV in a single cell, to as many as 1,000 copies of Pol IV in a cell. They also learned that levels of Pol IV were about as low in E. coli strains missing a functional sigma-38 as in normal strains growing in non-starving conditions. This led Foster and Layton to conclude that sigma-38 helps control to what extent Pol IV is expressed.

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Foster's and Layton's study was supported by a grant from the National Institute of General Medical Sciences (U.S.P.H.S. grant N.I.H.-N.I.G.M.S. G651575).

"Error-prone DNA polymerase IV is controlled by the stress-response sigma factor, RpoS, in Escherichia coli," Molecular Microbiology, vol. 50, no. 2; pp. 549-561

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• Bacteria
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• Escherichia coli
• Mutation
• Allele frequency
• Endospore
• Heat shock protein
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