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Scientists
snap first 3-D pictures of the "heart" of the transcription
machine
09
Dec 1999
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Berkeley
scientists have obtained the first good picture of a major chunk
of the machinery that turns genes on and off.
With
the help of electron microscopy and a relatively new technique
called single particle image analysis, the researchers reconstructed
a three-dimensional picture of the heart of the machine -- the
part that binds to DNA and starts the process of gene transcription.
The
picture shows for the first time how the proteins are arranged,
and gives clues to the inner workings of the machinery that
transcribes genes -- the complex of proteins that latches onto
and copies DNA into an RNA blueprint for building proteins.
"For
now, this is very basic, very fundamental research that helps
us understand how the machine works," said team leader Eva Nogales,
an assistant professor of molecular and cell biology at UC Berkeley
and a scientist at the Lawrence Berkeley National Laboratory.
"But it has implications for the treatment of disease, since
essentially treatment comes down to modifying the behavior of
proteins. One way to do that is to regulate transcription, which
is why proteins involved in transcription are a major target
for drug development."
The
results will appear in the Dec. 10 issue of the journal Science.
How it works
The
entire machine that transcribes a gene is composed of perhaps
50 proteins, including RNA polymerase, the enzyme that converts
DNA code into RNA code. A crew of transcription factors grabs
hold of the DNA just above the gene at a site called the core
promoter, while associated activators bind to enhancer regions
farther upstream of the gene to rev up transcription.
Working
as a tightly knit machine, these proteins transcribe a single
gene into messenger RNA. The messenger RNA wends its way out
of the nucleus to the factories that produce proteins, where
it serves as a blueprint for production of a specific protein.
The
new detail is of the proteins forming the very large complex
that binds DNA.
"We've
never had a picture of this entire complex, and it tells us
a lot about how this huge molecular machine works," said Robert
Tjian, professor of molecular and cell biology and an author
of the paper. The vast majority of work reconstructing the cell's
transcription machinery has been done by Tjian and his colleagues
at UC Berkeley over the past two decades. Both Tjian and Nogales
are part of UC Berkeley's Health Sciences Initiative, a research
effort that draws scientists from both the physical and biological
sciences into the search for solutions to today's major health
problems.
Tjian
and Nogales admit that the picture now revealed is the first
step in a long-term project to determine the three-dimensional
arrangement of all the proteins in the machine, in enough detail
to see the individual amino acids that make up each protein.
"The
resolution we have now is good enough for learning about how
things happen in the cell, but drug design comes with atomic
modeling at a much finer resolution -- about 10 times better
than we have now," Nogales said.
Nogales
now is at work sharpening this picture of the complex. She and
postdoctoral fellow Frank Andel III could not use standard X-ray
crystallography to determine the structure of these proteins
because the complex is about 10 times too big and the quantities
they can obtain from the nucleus about a thousand times too
small for that technique.
Postdoctoral
fellows Andreas G. Ladurner and Carla Inouye from Tjian's lab
also are authors on the paper.
Source:
Robert Sanders, Public Affairs
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Berkeley's
Health Sciences Initiative
Berkeley
Molecular & Cell Biology
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Lab
Science
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