New Enzyme Copies DNA in a Pinch, but its Mistakes Cost Us

------------------------------------------------------------------The University of Texas Medical Branch at GalvestonPublic Affairs Office301 University Boulevard, Suite 136, Galveston, Texas 77555-0802(409) 772-2618 (800) 228-1841------------------------------------------------------------------DATE: Aug. 29, 2000 CONTACT: Alana Mikkelsen, Public Affairs; (409) 772-8774 or (800) 228-1841; [email protected]

EMBARGOEDNot for release until 1 p.m., Central Time, on Wednesday, August 30.

SOURCES:For comment, contact Satya Prakash at (409) 747-8602 or [email protected]

NEW ENZYME COPIES DNA IN A PINCH, BUT ITS MISTAKES COST US

GALVESTON, Texas -- Our cells endure constant assault. Toxins, the sun's ultraviolet light, and even breathing and normal bodily functions produce chemical reactions that damage our genetic material. Until recently, scientists thought this routine genetic damage made it impossible for cells to make copies of their DNA, a step necessary for cells to reproduce. But new evidence, published in the Aug. 31 issue of Nature, suggests that certain DNA-copying enzymes have the ability to copy straight past DNA damage, even though that action will change the organism's genetic code and possibly cause cancer and other ailments down the road.

That finding -- made by geneticists Robert Johnson, Todd Washington, Lajos Haracska, Satya Prakash and Louise Prakash of the University of Texas Medical Branch at Galveston -- offers new insight into how higher organisms deal with genetic damage and how cancers are caused. It also underscores the extent to which evolutionary pressures emphasize the passing on of genes while tolerating -- and in some cases encouraging -- potentially deadly genetic mistakes.

Ultraviolet light, toxins and other damaging agents disrupt DNA's normal, spiral staircase structure in many ways. Sometimes, they cause kinks in the chemicals that form the steps of the staircase. Other times -- up to 10,000 times per day in a single cell -- they cause a step to fall off, creating a hole in the genetic code. When DNA-copying enzymes called polymerases encounter this damage, they usually fall off the DNA, thereby protecting the cell from genetic mistakes. (Making DNA copies from damaged genetic material would be like making photocopies of a smudged bicycle assembly sheet: the instructions would be hard to read, and the bicycle -- or, in our cells' case, the proteins that do our body's work -- might not come out right.)

Scientists used to think that the only way to get around this stalled DNA copying was for special DNA repair enzymes to fix the damage. But last year, members of the Prakash lab discovered a DNA polymerase that could copy past small, minor kinks in DNA's staircase without introducing mistakes into the genetic code. Publishing their observations in Science, they named the enzyme DNA polymerase "eta" after the seventh letter of the Greek alphabet, because it was only the seventh DNA polymerase then known. In the new Nature paper, several members of the same team describe the ninth DNA polymerase, iota, which plows easily through major kinks in the DNA staircase that DNA polymerase eta can't handle. Adding to the intrigue, the team found that iota is so dedicated to copying past major DNA damage that it won't copy DNA correctly under normal circumstances.

"We didn't ever think polymerases could be so specialized," says Satya Prakash, a senior author on the paper and a scientist with UTMB's Sealy Center for Molecular Science. His team also identified the eighth DNA polymerase, theta. (Its function is still a mystery, but like most DNA polymerases, it can't copy past genetic damage.)

The new evidence also lets off the hook another DNA polymerase, called zeta, which scientists had previously associated with high levels of genetic mutation, or changes in DNA. Such changes can lead to cancer that arises decades after the original genetic damage. And though scientists used to think that zeta actually caused the mutation, the UTMB team found instead that zeta is guilty only by association with the new DNA polymerase, iota. According to their work, it's iota that introduces mutations, in its effort to copy past major DNA damage occurring at or near the time a cell is copying its DNA. Then, after inserting an incorrect chemical at one end of a DNA step, iota falls off and zeta continues copying along the undamaged DNA chain.

"DNA polymerase zeta is like the driver of a getaway car," says Satya Prakash. "It doesn't commit the robbery, but it's an accessory to the crime."

In all, the recent findings lend new perspective to the age-old concept of a certain evolutionary trade-off: The point of life is to reproduce, not necessarily to do it perfectly. From many scientists' perspective, this trade-off is the reason that higher organisms get cancer and other ailments that occur after reproductive age.

"Once the period of reproduction is over, life is over, as far as evolution is concerned," says Satya Prakash. "Mutations cause cancers," he adds, "but they allow cells to live. They are the price we pay for living; that's how we have evolved. If we didn't have mutations to begin with, things would be static."

Now that scientists know more about how those mutations arise, says Prakash, they'll be better prepared to intervene in this process, perhaps preventing cancer and other genetic ailments in the future.

--UTMB--