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MIT Researchers Report Finding 1st Example of Biological Role for Z-DNA

Discovery comes in Professor Alexander Rich's lab where Z-DNA was first described nearly 16 years ago

CAMBRIDGE, Mass.--In 1979, researchers at the Massachusetts Institute of Technology, led by Professor Alexander Rich, startled the world of structural biology with the announcement that they had found a "left-handed" form of the basic genetic molecule of life, DNA. The new form, coiled in the shape of a left-handed screw, was called Z-DNA because of its zig-zag backbone, but its purpose remained a mystery for many years.

Today, MIT researchers led by Professor Rich report in the current issue (Aug. 1) of Proceedings of the National Academy of Sciences the discovery of the first biological role for left-handed Z-DNA.

Research Scientist Alan G. Herbert and his colleagues Ky Lowenhaupt and Jeffrey Spitzner with Professor Rich have identified a protein that binds tightly to Z-DNA. The protein, double-stranded RNA adenosine deaminase, has long been recognized as an "editor" of the genetic message. Its affinity for Z-DNA may help it find genes that are producing the messenger RNA which it "edits".

The enzyme is known to work by changing adenine, one of the four components of nucleic acids, so that it acts as if it were guanine, another of its components. This changes the information carried by the RNA from the nucleus of the cell to the cellular machinery.

In a commentary on the work, Professor Rich said:

"The left-handed form of DNA is less stable than the right-handed form, and it needs energy to be pushed into that form. One of the major sources for this energy comes from the movement of the enzyme that makes a copy of the genetic message which is then used in synthesizing proteins. This enzyme, called RNA polymerase, makes messenger RNA by moving along the right-handed DNA duplex. However, as other researchers have shown, instead of rotating around the DNA, it plows straight through. This leaves behind it DNA in an underwound or negatively supercoiled form. It has been found that the energy of this negative supercoiling can stabilize left-handed Z-DNA. Formation of Z-DNA may act as a signal to the editing enzyme that the information in the DNA is to be modified."

The activity of this editing enzyme causes a change in the amino acids found in a protein. One of the proteins in which this process is known to occur is an important ion channel found in the central nervous system. This ion channel, which has a receptor for glutamate, is known to transmit rapid excitatory impulses between cells. As other scientists have shown, the message for this protein is edited so that a different amino acid is substituted in part of the ion channel, and that confers on it its specific physiological response, Professor Rich said.

The enzyme acts only on double-stranded RNA. The messenger RNA which is produced must fold back on itself to make a double-stranded segment for editing to occur, but it is well known that messenger RNA is spliced so that some segments are eliminated.

"In the case of the glutamate receptor," Professor Rich said in his commentary, "other researchers have shown that part of the folded-back RNA segment comes from a piece that is eventually spliced out, so that it is no longer used in producing protein. Thus, the editing activity must occur before the RNA is fully processed to the form that is translated."

The question is, how does the enzyme find genes that are actively transcribing information so that it can rapidly carry out its editing function before splicing occurs?

In answering that question, the MIT paper points out that the enzyme binds strongly to Z-DNA, which is formed only in actively transcribing genes. "Thus, genes that are silent and not being expressed do not have Z-DNA in them. Only the genes that are being expressed have it, as only they have the RNA polymerase molecule moving along the DNA," Professor Rich said.

"Hence, the Z-DNA binding domain on this enzyme may facilitate its finding genes that are actively transcribing and producing messenger RNA. This allows the enzyme to carry out its vital editing function."

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