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Gene-duplicating proteins isolated.

Like a cook sharing recipes, a dividing cell must copy its DNA -- which contains instructions for how to make all of its proteins--and pass the information on to its offspring. But what tells the cell where to begin copying this genetic cookbook? And exactly how does the cell perform the Herculean task of reproducting it?

Roughly 20 years ago, molecular biologists discovered specific proteins that start the DNA-copying process in viruses and bacteria. The proteins bind to a certain stretch of these simple organisms' DNA, which comes in the form of a single circle. Since then, scientists have struggled to understand how higher organisms--whose much larger quantity of DNA comes tightly wound in multiple bar-like structures called chromosomes --copy their genes.

Now, biologists Stephen P. Bell and Bruce Stillman at Cold Spring Harbor (N.Y.) Laboratory have isolated a cluster of proteins that initiates copying of the chromosomes of baker's yeast. At a conference on the cell life cycle held at the laboratory last week, they predicted they will soon find that a similar protein complex initiates copying the genes of other higher organisms, from fruit flies to mice and humans. Compounds that block this process, they add, might prove useful as anticancer drugs.

Earlier this year, Stillman and Cold Spring Harbor researcher York Marahrens identified a set of so-called origin DNA sequences, where DNA replication in yeast begins. In the new discovery, Bell and Stillman have found a complex of seven proteins that binds to these origin sequences, setting the replication process in motion.

Bell and Stillman used a technique called DNA "footprinting" to track down the new proteins. Unlike DNA fingerprinting, which can highlight tiny discrepancies between the genetic material of two individuals, DNA footprinting reveals where proteins stick to DNA. Such DNA-binding proteins usually serve to turn genes on or off.

The researchers treated origin DNA sequences from yeast with an enzyme that chops DNA into fragments. When they sorted the DNA fragments by size on a gel and exposed the gel to photographic film, the different-size fragments showed up as a ladder of dark smears.

At several places in the ladder, Bell and Stillman observed missing rungs. These gaps indicated the presence of DNA-binding proteins, which protected the DNA from cleavage by the enzyme. The researchers, who also report their finding in the May 14 NATURE, named the proteins they isolated ORC, for origin replication complex.

"We propose that this complex initiates DNA replication in yeast," Stillman says. "And ... we believe that it has been conserved through evolution and appears in the cells of other [higher animals], including humans."

An experiment by two researchers at the Imperial Cancer Research Fund in Hertfordshire, England, has already confirmed the findings of Bell and Stillman. Using a different approach, John F. X. Diffley and Julie H. Cocker reported at the conference and in the same issue of NATURE that they have found the signature footprint of ORC on yeast DNA.

Joachim J. Li of the University of California, San Francisco, who also studies DNA replication, says the discoveries constitute "a quantum leap to a new level" in understanding how the cells of higher organisms copy their genes. He asserts that the findings should enable researchers to work backward and discover what prompts a cell to start replicating its DNA, and to figure out how a cell knows to stop after making only one copy.

Stillman says the discoveries might lead to new types of anticancer drugs, because cancerous cells must replicate their DNA more rapidly than normal cells in order to create tumors. "I don't think it's completely off the wall to think about new protein complexes like this as potential targets for chemotherapies," he says. "It's certainly something that should be looked at by drug companies."
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Title Annotation:origin replication complex
Author:Ezzell, Carol
Publication:Science News
Date:May 23, 1992
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