Letters to the Genetic Editor


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Profs. Ruth and Joseph Sperling. Stop and cut signs


Editors are a ruthless breed. They take a text the writer worked hard to produce, then heartlessly cut and paste, sometimes taking out entire paragraphs. All this is done for "editorial reasons"that no one can quite define. But the truth is, the editors are not to blame. They are simply following rules similar to those found in the most fundamental processes of nature, such as the transfer of genetic information from the cell's nucleus to other parts of the cell, where it is put to use.

For many years, biologists believed such information was meticulously preserved. With time, however, it became clear that on its way from the genes to the ribosome (the cellular structure that reads the information and uses it to manufacture proteins) the genetic text undergoes comprehensive editing. An understanding of this "editorial process"may help to clarify the factors involved in the development of various genetic diseases.

In the early 1960s, scientists believed that protein manufacture began when the closely intertwined double strands of DNA in the cell's nucleus unfurled, leading to the production of a new single strand (messenger RNA), which contained a "photocopy"of the genetic code. This strand traveled from the nucleus to the ribosomes in the cell, which then read the code and created proteins.
While this chain of events is true for bacteria, the picture is much more complicated in higher organisms. The American scientist Phillip Sharp and his British counterpart Richard Roberts discovered the existence of intermediate processes that resemble the way texts are edited and proofread before appearing in print. They found that the messenger RNA molecule was not a faithful copy of the DNA from which it was derived. There is a "pre-messenger" RNA molecule that indeed copies the DNA precisely, but some of its parts are cut out. The remaining parts come together and cling to one another, creating a "new genetic order," the messenger RNA molecule.

It later became clear that the removed parts, called introns -  those tossed to the "cutting room floor"-  carry no information for building proteins. The remaining parts, called exons, are the ones that, by connecting to one another, create the "real" genetic sequence that encodes the information needed to build the protein. Sharp and Roberts were awarded the 1993 Nobel Prize in Physiology or Medicine for their work.

End quote

But how can nature tell apart the exons, which contain the genetic information, from the introns, which carry irrelevant text? A once prevalent view was that each intron begins with a sequence of eight genetic letters, a command saying "end quote"or simply, "cut here!  "Later, however, it became clear that many such commands -  the same eight letters in the same order -  appear inside the introns themselves as well. In other words, the genetic "cut!" command also appears in many places where a cut would cause the creation of a defective, potentially toxic, protein. How then does nature distinguish between the "cut! "commands that must be executed and the "cut!" commands that should be ignored?

This is where Prof. Joseph Sperling of the Weizmann Institute of Science's Organic Chemistry Department and his wife and colleague Prof. Ruth Sperling of the Hebrew University of Jerusalem's Genetics Department enter the picture. Together with their teams, the Sperlings discovered that the undesirable "cut!" command is preceded by one of three three-letter genetic sequences: TAA, TAG, or TGA. These sequences function as genetic "stop signs." The scientists propose that the appearance of one of these stop signs, together with an eight-letter "end-of-quote" sequence, cancels the cut command. The scientists tested their hypothesis in a computer model using 446 human genes and found that in the vast majority of cases (98%) one of the stop signs appears before the eight-letter end-of-quote sign in places where cutting would lead to the production of toxic proteins.

In a series of experiments conducted to test this discovery in human tissue culture, the scientists placed one of the stop signs in various locations in the genetic code before a natural end-of-quote sequence. By so doing, they prevented the cutting that would have normally taken place. In a complementary series of experiments, they managed to perform the opposite process: They removed the natural stop sign, causing cuts to occur in places where they would not normally have taken place. Their findings were published in the Proceedings of the National Academy of Sciences (PNAS). The research team included postdoctoral fellow Dr. Binghui Li and graduate students Chaim Wachtel and Elana Miriami of the Hebrew University and graduate student Galit Yahalom of the Weizmann Institute.

Until now, most scientists believed that systems capable of deciding where to begin reading a strip of genetic information (such as the ribosome) existed only outside the nucleus. The Sperlings'findings, however, suggest that this kind of discretion (called the recognition of a "reading frame") takes place inside the nucleus as well. They have shown that the decision where to cut and paste introns and exons in pre-messenger RNA relies on an earlier choice regarding where the reading process begins. These unexpected findings are becoming the focus of numerous new studies in this field.

Finding the "stop" sign

Prof. Joseph Sperling's research is supported by Ms. Lois Zoller, Chicago, IL; Ms. Ruth Simon, Wilmette, IL; the Oscar and Emma Getz Trust, Chicago, IL; the Joseph and Ceil Mazer Center for Structural Biology; and the Helen and Milton A. Kimmelman Center for Biomolecular Structure and Assembly. He holds the Hilda Pomeraniec Chair of Organic Chemistry.