Sunny delight?



 

Does this boy have enough polymerase eta?

©1999, David Tenenbaum.











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Molecular sun worshipper
8 JULY 1999. Sunlight -- some people can't live without it. People who suffer from xeroderma pigmentosum (XP) can't live with it. In this rare genetic disease, tiny doses of sunlight trigger deadly skin cancers. For people with XP, night time is the right time for partying and camping. boy on beach
Now, researchers at the University of Texas Medical Branch at Galveston have identified a mechanism that allows most people to bask -- at least occasionally -- in the sun. It's apparently the same mechanism whose absence causes the growth of skin cancers in one form of XP.

The new finding could help explain why, early in the history of multi-cellular life, living things finally left the ocean and survived on land -- without getting fried by ultraviolet rays.

Copy right.
The mechanism in question is a newly discovered DNA polymerase. These enzymes reproduce DNA -- the cellular memory -- before a cell divides to make two new cells.

DNA polymerases have an exacting assignment. If DNA does not divide, life stops. But if damaged DNA divides, cancer can start. Faced with such a dismal dilemma, nature apparently invented the newly discovered enzyme, called polymerase eta, more than 300 million years ago.

In research published in February, Louise and Satya Prakash, and their colleague Robert Johnson, showed that polymerase eta could accomplish the seemingly impossible task. Confronted with a section of DNA damaged by ultraviolet (UV) light, most of the known polymerases stopped cold. The DNA didn't divide, converting the cell into a dead branch rather than a trunk of the tree of life.

Equally bad, another polymerase did replicate the damaged DNA, and with it the same genetic mistakes, or mutations. As Satya Prakash notes, as the number of mutations rises, cancer becomes more common. It's sort of like copying your neighbor's answers on a test -- it only works if you're peeking at an accurate original.

The February article documented that polymerase eta could sidestep the awful dilemma by reading and replicating the damaged DNA. "It does not know the difference between damaged and non-damaged," says Prakash.

Unlike known polymerases, however, it made corrections as it copied. That's like reading a neighbor's erroneous answers -- and scribbling the correct results!

It's the yeast you could do...
That work was done with a simple cell -- a yeast, to be exact. It's a long jump from yeast to people -- about 300 million years of evolution. Acting on a hunch, the Texas researchers decided to search for the gene that made polymerase eta among those XP patients who get skin cancers because they cannot copy DNA accurately.

The hunch paid off -- the polymerase eta gene was not working, indicating that a lack of this "repair and replicate" enzyme is responsible for the skin cancers caused by XP.

Prakash explains that the UV in sunlight damages DNA by causing an unwanted bond between adjacent thymine units. (DNA is a gigantic string of the letters T -- standing for thymine, and A, C, and G. These letters serve as templates for the production of proteins. When enough flaws accumulate in genetic code, a cell can die or become cancerous.)

When adjacent thymine units are bonded, most polymerases lay down their shovels and quit copying, but polymerase eta kept right on trucking. "Even though the DNA is distorted, this polymerase is able to extract the right information and copy the DNA correctly, so you won't have a mutation," says Prakash.

The new discovery is significant, says John Petrini, associate professor of genetics at the University of Wisconsin-Madison. "It's there to ensure against mutations," he says. "It's intuitively obvious [that such a mechanism would have evolved]. But demonstrating that is exciting because it's often impossible to prove things -- intuition is so often wrong."

The finding helps answer a vexing question: How did life emerge from the ocean? The gene for polymerase eta, it turns out, is extremely widespread in the animal and plant kingdoms, Prakash says, indicating that "It's a very important mechanism that allows us to live in sunlight." (Curiously, a second mechanism is the ability to repair DNA when cells are not dividing. The lack of this mechanism causes a second form of XP.)

In the short term, the discovery is basic research that will not close down Camp Sundown, the nighttime camp for kids with XP. In the long term, knowing how damaged DNA replicates itself correctly may have practical benefits, such as a better diagnosis or even treatment of XP. Eventually, it could become the basis of genetic therapy -- after someone figures out how to transfer the polymerase eta gene into XP patients.

The finding could have significance for the rest of us, if, as Prakash suggests, a low concentration of polymerase eta explains other cases of skin cancer. Furthermore, as Petrini notes, evidence that polymerase's ability to repair DNA in tissues not subject to sunlight could have implications for research into aging and degenerative diseases. Polymerases that repair DNA "are present in all tissues," Petrini says. "They are not just expressed in tissue exposed to sunlight." Researchers have already found that the lack of certain DNA repair enzymes in mice leads to premature aging.

At any rate, given the ongoing destruction of stratospheric ozone, which blocks UV radiation, the discovery could eventually help surfers and other sun-worshipers survive the rigors of life out of the ocean.

--David Tenenbaum

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The Why Files Efficient Bypass of a Thymine-Thymine Dimer by Yeast DNA Polymerase eta, Robert E. Johnson et al, Science, 12 February 1999, pp. 1001-4.

hRAD30 Mutations in the Variant Form of Xeroderma Pigmentosum, Robert E. Johnson et al, Science, 9 July 1999, pp. 263-5.

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