Caltech Biologists Pin Down Chain of Reactions That Turn On the Duplication of DNA

PASADENA—Caltech biologists have pinpointed the sequence of reactions that triggers the duplication of DNA in cells.

In companion papers appearing in recent issues of the journals Science and Cell, Assistant Professor of Biology Raymond Deshaies and his colleagues describe the chain of events that lead to the copying of chromosomes in a baker's yeast cell. Baker's yeast is often used as a model for human cells, so the research could have future implications for technology aimed at controlling cell reproduction, such as cancer treatments.

"We've provided a bird's-eye view of how a cell switches on the machinery that copies DNA," says Deshaies. "These principles can now be translated into a better understanding of how human cells proliferate."

The group's research keys primarily on how cells copy and segregate their chromosomes during the process of duplicating one cell into two. The new papers are concerned with how cells enter the DNA synthesis phase, during which the chromosomes are copied.

A question that cell biologists have sought for years to answer is that of which precise chemical events set off these reactions. The cell cycle is fundamental to the growth and division of all cells, but the process is somehow ramped down once the organism reaches maturity.

The paper appearing in Science describes how DNA synthesis is turned on. In the preceding stage (known as G1), proteins named G1 cyclins trigger the destruction of an inhibitor that keeps DNA synthesis from beginning.

This inhibitor sequesters an enzyme referred to as S-CDK (for DNA synthesis-promoting cyclin-dependent kinase), thereby blocking its action. Once the S-CDK is released, it switches on DNA synthesis. The S-CDK is present before the copying of DNA begins, but the DNA copying is not turned on until the S-CDK is freed of its inhibitor. The Deshaies group has shown that several phosphates are attached to the S-CDK inhibitor. These phosphates act as a molecular Velcro, sticking the inhibitor to yet another set of proteins called SCF.

The Cell paper essentially picks up on the description of the cell cycle at this point. The SCF, which acts like a molecular "hit man," promotes the attachment of another protein, ubiquitin. Ubiquitin in turn attracts the cellular garbage pail, proteasome. The inhibitor is disposed of in the proteasome, thereby freeing the S-CDK, which goes on to stimulate DNA duplication.

The process described above is quite complicated even in this condensed form, and actually is considerably more complicated in its technical details. But the detailed description that Deshaies and his colleagues have achieved is important fundamental science that could have technological implications in the future, Deshaies says.

"This traces the ignition of DNA synthesis down to a relatively small set of proteins," he says. "Any time you figure out how a part of the cell division machinery works, you can start thinking about devising new strategies to turn it on and off."

It is a precise turning on and off of DNA replication, many researchers think, that will someday be the key to better and more specific cancer-fighting drugs. Because a tumor is a group of cells that literally never stops the cell duplication cycle, a greater understanding of the cycle itself is almost certain to be a factor in further medical advances in cancer treatment.

"It could be five to 10 years, but this work could point the way to new cancer-fighting drugs," Deshaies says. "It is much easier to begin a rational approach to developing new treatments for cancer if you are armed with fundamental insights into how the cellular machinery works."

The other authors on the paper in the October 17 issue of Cell are R. M. Renny Feldman, a Caltech graduate student in biology; Craig C. Correll, a Caltech postdoctoral scholar in biology; and Kenneth B. Kaplan, a postdoctoral researcher at MIT.

The other authors of the Science paper from the October 17 issue are Rati Verma, a senior research fellow at Caltech; Gregory Reynard, a Caltech technician; and R. S. Annan, M. J. Huddleston, and S. A. Carr, all of the Research Mass Spectrometry Laboratory at SmithKline Beecham Pharmaceuticals in King of Prussia, Pennsylvania.