Mutate Or Die: New Polymerase Gives Desperate Yeast An Option

June 14, 1996

Biologists have discovered the first of a new DNA polymerase family: a last-gasp enzyme that yeast cells turn to when all attempts to fix damaged DNA have failed. The enzyme increases a cell's odds at staying alive, but it does so by dramatically boosting the type of mutations that, in humans and other animals, sometimes become the genetic seeds from which cancers grow. The research by the University of Rochester team, done by creating in yeast the type of damage that sunlight does to our own DNA, is reported in the June 14 issue of Science.

The findings shed new light on how yeast and probably other organisms cope with damaged DNA, a constant, potentially dangerous problem for yeast and humans alike. Damaged DNA that is copied to other cells carries a much greater risk of causing cancer and other diseases than healthy DNA does. By copying damaged DNA, the new enzyme serves as a fountain of mutations; corking it would be one way to prevent damaged DNA from propagating and to squelch genetic mishaps before they develop into full-blown disease.

The enzyme, dubbed "zeta," is a member of the first new eukaryotic DNA polymerase family to be discovered in about a decade and is the first polymerase whose purpose is to allow an organism to tolerate, rather than fix or discard, damaged DNA. Unlike other polymerases, which either refuse to copy damaged DNA or which help repair it, zeta lets a cell replicate damaged DNA, giving the cell a chance at life at the cost of a higher mutation rate for the organism.

"Replicating past the damaged site is the least favored mechanism of dealing with DNA damage, but from the cell's perspective, it's better to replicate damaged DNA and survive than to not replicate and die," says Christopher Lawrence, professor of biophysics. Working with Lawrence on the project, funded by the National Institutes of Health, are research associate John Nelson in the Department of Biophysics, and David Hinkle, associate professor of biology.

There have been hints of a previously unknown polymerase in yeast, but only with recent technology could Nelson, working with Hinkle and Lawrence, prove it by purifying the enzyme and demonstrating its function.

Mutant yeast without the enzyme are slightly more likely to die than their zeta-carrying counterparts, but they're also far less likely to suffer detrimental mutations. Indeed, yeast that lack one of the two genes that code for the enzyme have only about 5 percent as many mutations as "normal" yeast.

Mutations are a risk wherever there is damaged DNA -- and damaged DNA is an unavoidable fact of life. It comes not only from cigarettes, sunlight, and other factors, but also happens naturally and constantly as the body's cells replicate the seven-foot strand of DNA that's in all our cells.

More than 99 percent of DNA damage in our bodies is fixed by special repair enzymes. But sometimes these repair enzymes can't keep up with the damage, or the damage is so severe that even the body's internal editors can't fix it before replication occurs.

Unrepaired damage usually stymies polymerases, which normally zip along a section of DNA, copying nucleotides uneventfully and assembling new strands of DNA. Zeta, however, is at least 10 times more efficient at getting around these impasses, somehow replicating past unrepaired sites. This keeps the cell alive, but it increases the odds of a mutation.

"This is a last-gasp system," says Hinkle. "For the cell, it's better to mutate than to die."

Lawrence believes that this process accounts for 2/3 to 3/4 of all spontaneous mutations in yeast, including base substitutions, the type often seen in cancer cells or oncogenes like p53 or ras in humans. His laboratory is now searching for counterparts in humans to the two genes that code for zeta, and scientist Peter Gibbs has found one whose sequence bears the markings of a zeta polymerase. If zeta is found in humans and works similarly, it would be an attractive target for anti-cancer therapies.

"If this does work the same way in humans, then it's conceivable that some day we could inhibit this enzyme in people prone to mutations, such as those receiving chemotherapy or people with a genetic history of cancer," says Hinkle.

The team performed the study by using ultraviolet light to intentionally cause a well-placed defect, or lesion, in DNA. The defect is a thymine-thymine dimer, a very common and well studied lesion created when sunlight hits an organism, causing two bases to link up unnaturally. The abnormality almost always stops other polymerases dead in their tracks, but zeta went past the dimer about 10 percent of the time.

"Ultraviolet damage to DNA is the process that leads to skin cancer," says Nelson. "Sunlight is always causing DNA damage, and humans have a good system for fixing it. But when there's a lot of damage, the repair system is just overwhelmed, and the body tries other ways to cope. This zeta polymerase is one such last- ditch effort."

University of Rochester

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