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Ubiquitin Strikes Again

For versatility, it's hard to beat ubiquitin. Found virtually unchanged in organisms from yeast to humans, the little protein participates in myriad cellular processes, including cell division, DNA repair, and programmed cell death. In a paper published online this week by Science, researchers show that in addition to all that, ubiquitin may act as a kind of stopwatch for proteins that switch genes on or off.

One of ubiquitin's best-known roles is to help clean up the cell. Specialized enzymes called ubiquitin ligases attach a chain of ubiquitin molecules to unwanted proteins; the chain alerts a complex called the proteasome, which chews up the protein. This happens to transcription factors, after they have turned genes on; so ubiquitin, in effect, turns the genes off. Curiously, previous research by molecular biologist William Tansey and his colleagues at Cold Spring Harbor Laboratory in New York had suggested that ubiquitin might also be involved in starting DNA transcription.

Puzzled, the group set out to see what would happen to transcription if ubiquitin-adding enzymes were taken off the scene. The team first made yeast cells produce a modified version of VP16, an easy-to-study viral transcription factor that's often used in research. When they knocked out the yeast's Met30, one of the ubiquitin ligases, VP16 remained ubiquitin-free, and it lingered inside the cell rather than being chewed up as usual. But something else happened, too: without Met30, VP16 could no longer activate transcription. The team carried out several control experiments to make sure that VP16 was working fine otherwise, and that it was really the missing ubiquitin that kept it from switching on DNA transcription.

Tansey thinks this need to attach ubiquitin before transcription can begin serves a purpose. "It's like the cell is granting a license to the protein for a certain period of activity, before it gets destroyed," Tansey says. "The clock is ticking, and it's going to get eaten up very quickly."

"It's a great piece of work," says biochemist Alexander Varshavsky of the California Institute of Technology in Pasadena, a pioneer in ubiquitin research. He calls the report "one of the most remarkable--and unexpected--discoveries of the past decade." Indeed, Tansey says, the result is so counterintuitive that it's meeting enthusiastic support as well as passionate opposition. "This research has generated the most emotional response I've ever seen."

Related sites

William Tansey's home page
The ubiquitin system, from Nottingham University
More on the ubiquitin system
Abstract of Tansey's previous ubiquitin paper in the Proceedings of the National Academy of Sciences