June 11, 1999 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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