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NSF PR 99-41 - June 10, 1999
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'Altered State' May Be Responsible for Creating Important
Brain Chemicals
Twenty years after visualizing a surprising left-handed
form of the DNA double helix, Massachusetts Institute
of Technology researcher Alexander Rich has found
that this altered form of genetic material is involved
in some important biological activities, including
creating proteins essential for normal brain function.
Rich’s work is funded in part by the National Science
Foundation (NSF).
In the 1970s, when Rich and his colleagues solved for
the first time the three-dimensional structure of
a DNA crystal fragment, they were puzzled. Instead
of looking like the right handed double helix Watson
and Crick had described in 1953, the structure was
a left-handed double helix with an irregular zig-zag
backbone.
Is this unusual form of DNA, dubbed Z-DNA by the researchers,
an oddity or is it biologically significant? In this
week’s issue of the journal Science, Rich and colleagues
partly resolve the issue. They describe how the three-dimensional
structure of Z-DNA binds to a portion of an enzyme.
The enzyme binds to Z-DNA with great specificity,
leading scientists to conclude that the two serve
a biological function. The enzyme creates a modified
protein that is used by the brain as a receptor for
serotonin, among other things. Yet another striking
example of nature's ability to perform many functions
with the same materials, the protein bound to Z-DNA
is closely related in three-dimensional structure
to a family of proteins known to bind to right-handed
DNA.
"This work clearly demonstrates that DNA structure
is not symmetric or regular," explains Kamal Shukla,
program director for biophysics at NSF. “Rich’s results
will be important to a better understanding of gene
expression, viral DNA packaging and many other important
biological functions."
Adds Rich, "Twenty years after first visualizing a
left handed form of the DNA double helix, it may now
be possible to see ways in which nature uses this
altered form of the molecule to carry out important
biological activities."
Much has been learned about Z-DNA since it was first
discovered. It turns out that Z-DNA is found only
transiently when genes are actively being transcribed.
It occurs mainly in specialized sequences of nucleotides,
the building blocks of genetic material, and is stabilized
by processes that partially unwind the normal right-handed
DNA double helix. The main process that produces such
an unwinding is transcription (the synthesis of messenger
RNA), which is used as a template for assembling proteins
in biological systems.
The system works this way: When the enzyme making
RNA, called RNA polymerase, moves along the DNA double
helix, it leaves behind underwound DNA. Selected sequences
in this DNA temporarily become left-handed Z-DNA,
like a stretched phone cord coiling backwards on itself.
When the RNA polymerase stops moving, other enzymes
relax the DNA and it reverts to its normal right-handed
form. Like a stretched phone cord that is released,
it snaps back into its usual shape.
Rich’s work is also funded by the National Institutes
of Health.
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