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Celebrating cellular and scientific flexibility

By Kristen Garner

Was it good luck or brilliant insight? That's what Chuck Cole, Ph.D., a professor of biochemistry at Dartmouth Medical School, wonders about a recent discovery in his lab. He and former DMS graduate student Jack Scarcelli, Ph.D., started down one scientific path but ended up making an important, unexpected discovery that brought them onto a very different avenue. They identified a gene that plays a role in allowing the membrane surrounding the cell nucleus to stay flexible. And they showed that this flexibility is very important in the assembly of passageways that allow cellular messages to get in and out of the nucleus.

These passageways, nuclear pore complexes (NPCs), are tunnels made of proteins through the nuclear membrane. NPCs are important because, says Scarcelli, messenger RNA (mRNA), which encodes the proteins that carry outmany of the functions of the cell, is made from DNA within the nucleus—but the cellular machinery that makes the proteins is out in the cell's cytoplasm.

Studies: The discovery began with studies of how mRNA gets in and out of the cell—something Cole's lab has long been interested in. Scarcelli used robotics to do a large-scale experiment to identify genes in yeast cells that, when missing, cause a defect in the export of mRNA. From this screen, several genes were shown to affect mRNA export, including Apq12. At first the researchers thought Apq12 was directly involved in mRNA

Nuclear pore complexes (NPCs) are passageways through which cellular messages move. Researchers stained these NPCs to show that those lacking a protein called Apq12 (on the left) could not assemble the passageways the way normal cells can (on the right).

"In science," says Cole, "you have to follow the interesting results."

export, perhaps as part of the NPC. What they found, however, was quite different.

Hypothesis: When Cole and Scarcelli looked closely at Apq12's role, they saw that, in cells lacking it,NPCs could not be assembled correctly at low temperatures. At lower temperatures, cells adjust the makeup of the nuclear membrane to maintain its fluidity and flexibility. So the researchers hypothesized that yeast cells that lacked Apq12 no longer had the ability to alter the membrane's composition. To test the idea, they treated the cells with benzyl alcohol, a chemical that loosens up the membrane. After the membrane's flexibility had been restored with benzyl alcohol, the NPCs

could then be assembled correctly, even in the Apq12 mutants.

So a project that began with mRNA export ended with a discovery in nuclear membrane biophysics—a discovery that has garnered quite a bit of attention. The paper was published in the Journal of Cell Biology and featured in Cell's "Leading Edge" section. The researchers still don't know exactly how Apq12 changes the nuclear membrane's flexibility, but that's their next step.

"In science," says Cole, "you have to follow the interesting results that you get." Clearly, his and Scarcelli's ability to switch gears and follow unexpected findings has paid off. Instead of good luck or brilliant insight, maybe this finding is a credit to their ability to remain flexible.

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