Magazine article Science News

Crystal Clear: X-Ray Snapshots Illuminate How Enzymes Stitch Together DNA

Magazine article Science News

Crystal Clear: X-Ray Snapshots Illuminate How Enzymes Stitch Together DNA

Article excerpt

In 1953, James Watson and Francis Crick earned immortality in the annals of science by identifying the three-dimensional shape of deoxyribonucleic acid, better known as DNA--the chemical that makes up genes. In 1968, Watson set down his account of the race to this discovery in The Double Helix, a book whose title succinctly summarizes the structure of DNA.

This helical shape results from two intertwined strands of nucleotides, the building blocks of DNA. Watson and Crick argued that DNA's four nucleotides pair only in certain combinations--an adenine on one strand normally joins only to a thymine on the other strand, and cytosine pairs with guanine.

This complementary nature of the two DNA strands suggested a solution to a major mystery of genetics: How do cells copy their DNA?

"It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material," Watson and Crick noted in the remarkably reserved final sentence of their April 25, 1953 report in Nature.

A month later, the scientists made public their proposal that DNA's double helix unwinds its two strands, and the cell then reads the nucleotides on each and fashions the new, complementary strands.

In the years since, researchers have largely confirmed Watson and Crick's hypothesis and have identified the tools that cells employ in this process. Central among them are DNA polymerases, the enzymes that choose appropriate nucleotides and stitch them together into new strands of DNA. Some polymerases repair short spans of damaged DNA, while others duplicate whole genomes at a time.

"These are the enzymes that make copies of the blueprint of life," says Lorena S. Beese of Duke University Medical Center in Durham, N.C.

Now, by shining X rays at crystallized versions of the polymerases, a research group led by Beese and one led by Tom Ellenberger of Harvard Medical School in Boston have obtained high-resolution images of the enzymes' three-dimensional structures. With these pictures in hand, the investigators have begun to clear up the mysteries surrounding how these crucial proteins work.

"The results provide atomic-level detail of an enzyme that is incredibly important for maintaining the stability of genetic information," says Thomas A. Kunkel of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C.

"It's as if we're seeing frames from a movie, and if we get enough different shots, we will eventually get the whole story," adds Catherine M. Joyce of Yale University.

The story should be compelling, because polymerases often lie at the heart of gene mutations that can cause cancer or other diseases.

"One of the easiest ways for a mutation to arise is from a copying error by a DNA polymerase," says Kunkel. "It's really an important human health issue to understand how DNA is copied accurately."

Investigators have for many years created crystals of DNA polymerases and shone X rays through them to reveal the precise locations of the molecules' many atoms. While each polymerase has displayed its own unique shape, the images have inspired researchers to describe DNA polymerases in general as shaped somewhat like an open hand--that is, a palm, a thumb, and a set of fingers.

"Essentially, you have a flat part where the DNA sits and two appendages that kind of wrap around the DNA," explains Ellenberger.

Scientists believe that the palm holds a polymerase's active site, the region where the enzyme catalyzes the chemical reaction that joins a new nucleotide to a DNA strand. The DNA and the nucleotide bind to different regions of the polymerase, but the enzyme somehow brings them together in the active site.

Ellenberger and his colleagues may now have captured this climactic scene on film. In the Jan. 15 Nature, they publish an X-ray picture with all three characters--the polymerase, the target DNA, and the incoming nucleotide--of this genetic drama. …

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