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An unlikely assembly plant

Yale Medicine Magazine, 2003 - Winter


If the ribosome makes the body’s proteins, what makes it? Oddly enough, a giant.

Imagine that you’re out for a stroll in your neighborhood, passing the same familiar landmarks you see every day, when you suddenly come upon an enormous factory. Now imagine how astonished you’d be to learn that the behemoth had been there all along, but no one had been able to see it until now. That’s about how surprised Susan J. Baserga, M.D. ’88, Ph.D. ’88, was to find the cellular equivalent of an assembly plant hiding in plain sight.

Baserga and colleagues discovered and purified a new cellular entity, dubbed the SSU processome, which plays a key role in the making of ribosomes, the cellular machinery responsible for manufacturing all proteins. Surprisingly, the SSU processome, undetected until now, is nearly as large as a ribosome, about 80 Svedberg units.

“We were surprised to discover that it takes a complex as big as a ribosome to make a ribosome,” said Baserga, associate professor of molecular biophysics and biochemistry, therapeutic radiology and genetics. The SSU processome—a complex of RNA and many proteins—wasn’t detected until now because previous techniques used to look for RNA-protein complexes filtered out the larger ones, leaving only smaller material. “We were able to find it because we made our extracts—the starting material for purifying RNA-protein complexes—differently,” said Baserga. The mass spectrometry work of collaborator Donald F. Hunt, Ph.D., of the University of Virginia, also figured prominently.

The researchers, who reported their work last June in Nature, named the complex a processome “because it’s essential for processing the RNA that becomes part of the ribosome,” said Baserga. The “SSU” in the name stands for small subunit, because the complex is required for processing small ribosomal subunits, but not large ones. Though they’re not sure exactly how it functions, Baserga and co-workers believe the SSU processome and its proteins help fold ribosomal RNA into the proper configuration. It’s already known that the RNA portion of the ribosome is “the business end” that facilitates the ribosome’s protein-producing work, so properly processed ribosomal RNA is essential to the ribosome’s function, noted Baserga. The SSU processome appears to be so critical to cell growth and health, in fact, that Baserga suspects that defective processomes may be at the root of some diseases for which the causes are not well understood.

Researchers also are interested in the basic science behind RNA processing in all types of cells, Baserga added. “There’s pretty good reason to think that RNA was the first molecule, and that DNA and all the other molecules came from RNA. So studying anything that affects RNA metabolism brings you closer to understanding basic cellular processes.”

Next, the research team wants to explore how the SSU processome assembles into the huge complex it eventually becomes. “We think there’s a definite order of assembly,” says Baserga. Working with helicases—enzymes that fold and unfold protein and RNA—one of her students hopes to “freeze” the process in mid-course, providing a snapshot of assembly in progress. Baserga’s group will continue to tease out the exact details of how the SSU processome coaxes ribosomal RNA into the proper form. “That,” she said, “is going to be the next 10 years or so of work.”

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