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Keep it simple? No way, say cells

Hahn seeks to unravel mysteries of how genes get switched on - the process known as transcription
Neeman Mohibullah, Wendy Reeves and Dr. Steven Hahn examine a poster.
Neeman Mohibullah, Wendy Reeves and Dr. Steven Hahn examine a poster based on Hahn's research that explains how transcription-the process of gene expression-is reinitiated. Photo by Michelle Hruby

Simplicity, simplicity, simplicity. I say, let your affairs be as two or three, and not a hundred or a thousand; instead of a million count half a dozen, and keep your accounts on your thumbnail. - Henry David Thoreau

Cells don't listen to Thoreau. Just ask Dr. Steven Hahn of the Basic Sciences Division.

Nowhere is a cell's scorn for simplicity more evident than when it undertakes one of biology's most fundamental tasks, the process of switching on a gene.

In fact, every time a cell deciphers a single gene's DNA instructions, about 70 cellular jigsaw-puzzle pieces must assemble themselves into a functional machine that unzips a bit of the double helix and interprets the DNA letters into readable text for protein production. The same process occurs simultaneously for each of the hundreds, or even thousands, of genes whose use is required by the cell at any given time.

Hahn admits - and other scientists agree - that "the phenomenon has turned out to be much more complicated than we ever expected.

"When I first started working on this problem in 1987, I could carry around all the papers published on the subject in one folder," said Hahn, also an investigator of the Howard Hughes Medical Institute. "Now I've filled two big file cabinets."

What drives Hahn and others who strive to understand this intricate process, known as transcription, is that gene expression is central to virtually every biological process. Any significant defect in the system spells disastrous consequences, including death or disease. Indeed, aberrant gene expression of key growth regulators is a hallmark of many cancer cells.

Yeast as model

Complex biological problems such as this often prompt researchers to turn to model organisms, and transcription has been no exception. Hahn was one of the first to use the baker's yeast Saccharomyces cerevisiae to identify and characterize the essential components required to transcribe the DNA code into RNA, the messenger molecule that ultimately translates into protein.

One of his groundbreaking discoveries was to isolate in yeast the key protein (called TBP, for TATA-binding protein) that enables transcription to begin at the starting point of a gene. This crucial finding opened the field to a flood of new research to identify more protein components of the transcription apparatus.

While yeast affords many experimental advantages, as cells can be cultured quickly and mutant strains are relatively simple to construct, the transcription machinery of yeast turns out to be no simpler in design than that of human cells.

Transcription of any gene in a nucleated cell (those of organisms other than bacteria) depends on about 70 components, 12 of which form the actual enzyme-called RNA polymerase-that strings together the RNA molecule based on information in the DNA code.

In addition, a collection of other proteins known as general transcription factors ensure that RNA polymerase is positioned correctly at the start of a gene and is competent to modulate the amount and timing of gene expression in response to signals for growth and development.

This so-called basal-transcription machinery doesn't include what are known as gene-specific activator proteins, required to trigger or further boost low levels of gene expression when cellular or environmental conditions demand enhanced production. Such activated transcription is made possible by quick, successive rounds of genetic transcription.

Must a cell expend the energy to reassemble this entire complex for each round of gene expression? Hahn's recent research suggests not.

"Recruitment of all these factors is a relatively slow process, so it would make sense to leave some of them behind at the promoter (start point) when the cell needs to have high levels of transcription," he said. "And that's just what we've found."

In a study published in 2000, former graduate students Drs. Jeff Ranish and Natalya Yudkovsky showed that a core group of transcription factors - what they term a scaffold - remains at the gene's starting point to allow for rapid rebooting of the process. The scaffold, stabilized at the start site by gene-specific activator proteins, provides a template that enables RNA polymerase to find its way back to the promoter with ease, where it can begin the process anew.

Selective disruption

A major focus of Hahn's lab is to understand why cells require so many components to turn on a gene. One approach is selective disruption of components of the transcription apparatus, either by making mutations that affect individual proteins or with drugs that target steps of the process. Results of such studies often can reveal the crucial functions of each piece in the puzzle.

Most satisfying for Hahn would be to reconstruct a three-dimensional picture of the entire complex of proteins as it interacts with the DNA. In collaborations with X-ray crystallographers, in particular the late Dr. Paul Sigler of Yale University, Hahn's lab has been able to accomplish this goal for a subset of the most critical components. The lab also uses a technique called photo cross-linking, which uses chemicals to probe the nature of the interactions of proteins within the transcription complex.

Such studies provide Hahn with a view of "who's touching whom."

"This kind of three-dimensional approach allows us to understand how molecules work at a higher level," he said. "And if you want to conduct genetic experiments, which our lab does, the structure helps guide you to make targeted mutations. Both approaches are important."

Scientists are still uncertain as to what they would see if they were able to view the transcription process with an infinitely powerful microscope, although such detailed understanding may be years away.

"It's really beyond the capability of the technology we have right now," Hahn said. "But the ultimate goal would be to have an atomic-scale view of the process."

Sounds simple, doesn't it?


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