MADISON --Working with a common form of brewer's yeast, University of Wisconsin-Madison researchers have uncovered novel functions of a key protein that allow it to act as a master regulatory switch -- a control that determines gene activity and that, when malfunctioning in humans, may contribute to serious neurological disorders.

The work, published in the Dec. 8 issue of the journal Molecular Cell, shows how a mutation in a single gene can have widespread effects on regulation of the genetic program in a cell, causing some genes to be read more than normal and others less than normal.

While nearly every cell in an organism contains a complete set of DNA, each individual cell uses only a small fraction of that information at any given moment, explains David Brow, the senior author of the new study and a professor of biomolecular chemistry in the UW School of Medicine and Public Health. A host of proteins are responsible for controlling which genetic messages are read and how much of the information is used. Working with yeast, Brow and his colleagues show that a protein called Sen1 plays an important early role in this process.

Mutations in the human version of Sen1 are linked to neurological diseases, including a rare form of amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig's disease, and movement disorders. By exploring how Sen1 works in yeast, Brow provides a powerful tool other researchers can use to better understand the interplay of the protein and gene regulation in human disease.

"This work gives a method to start examining what the defect is in humans," he says.

In the past, says Brow, researchers looked at regulation of individual genes but not the whole genome at once. Using yeast, a small and relatively simple organism, the Wisconsin group developed a method to get a broad view of how Sen1 works and what happens when it doesn't work properly.

Normally, Sen1 acts like a molecular
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Contact: David Brow
dabrow@wisc.edu
608-262-1475
University of Wisconsin-Madison
7-Dec-2006