DNA or RNA? Versatile Player Takes a Leading Role in Molecular Research

For decades, DNA has been the star of molecular biology. But it is increasingly having to share the stage as biologists discover more about the versatility of RNA, long viewed as a mere copyist of the genes encoded in the famous double helix. Looked at from RNA's point of view, DNA is just a passive archive of information, a dull hunk of a telephone directory; it is RNA that looks up the numbers, establishes the connections and determines how long each call will last. "Anything DNA can do, RNA can do better," was the slogan on a slide shown by one biologist, Susan Gottesman of the National Cancer Institute, at a symposium at the Cold Spring Harbor Laboratory on Long Island. In the past, RNA did not get this kind of respect. The central dogma of biology has been that DNA makes messenger RNA, messenger RNA makes proteins, and proteins do everything else that needs to be done in a living cell. Though still unchallenged, that dogma has begun to seem less comprehensive, after an explosion of findings about regulatory RNA, a different sort of RNA that is produced by animal and plant cells and by viruses. Regulatory RNA is turning out to be a major player in some of a cell's most vital activities. It guards the integrity of the DNA in the egg and sperm cells that pass hereditary information to the next generation. It may help determine what genes are accessible to each type of cell, a crucial choice for multicellular animals that require a liver cell to read off one set of genes and a brain cell to be governed by a different set. And it coordinates suites of genes that may be under different control systems but need to act together in response to sudden stresses. The new regulatory role of RNA began to emerge in the last 10 years as researchers discovered a class of short RNA molecules known as silencing RNA's and a second class called micro-RNA's. The two classes have turned out to share many common features. Both are generated from short genes, or pieces of DNA, in the genome. And both, researchers found, follow a different career path from messenger RNA. With protein-coding genes, a copy of the gene's DNA is transcribed into RNA, and this messenger RNA, after processing, arrives at the cell's protein-making units where its information is used to manufacture a specific kind of protein molecule. In the case of regulatory RNA, the RNA transcript of a gene is processed by a baroquely named troika of enzymes known as Dicer, Slicer and Argonaute, the end result being a slew of short fragments of RNA some 20 or so units in length. Despite their brevity, these snippets of RNA are long enough to match specific sequences of RNA units within the cell's many different kinds of messenger RNA's. When the snippets find a match to messenger RNA, the micro-RNA's curb the activity of the messenger RNA's and the silencing RNA's destroy their messenger RNA targets. This means that much less or none of a protein gets produced in the cell. Having worked out how regulatory RNA's are generated, researchers are moving on to the next set of problems, which were the focus of last week's conference. One task is to catalog how many regulatory RNA genes exist in the cells of various species. Humans have more than 400 micro-RNA genes, the roundworm has 111 and the Arabidopsis mustard plant 133, David Bartel of M.I.T. said at the meeting. Though 400 micro-RNA genes may seem small in relation to the 25,000 protein-coding genes in a human cell, each micro-RNA can interfere with many kinds of messenger RNA. This imposes an evolutionary constraint on all the cell's messenger RNA's, because the genes that do not need their proteins to be controlled by micro-RNA must avoid evolving the sequences that are recognized by them. Dr. Bartel said he and colleagues estimated that more than one-third of human genes are under evolutionary pressure to maintain sequences in their messenger RNA's that can be controlled by regulatory RNA's, and many more must avoid acquiring such sequences. Because regulatory RNA's can influence so many messenger RNA's at a time, they are likely to play important roles. Regulatory RNA, particularly silencing RNA, is active in eggs and sperm, presumably because it is needed to guard the heirloom DNA from viruses and other elements that might subvert it. Regulatory RNA's are also involved in setting the chromatin state of a cell. Chromatin, the set of special protein spools around which each DNA molecule is wound, can be in an open state, meaning its genes can be read off by the cell, or in a closed state, in which its genes are silenced. Robert Martienssen, of the Cold Spring Harbor Laboratory, recently found that in the closed chromatin, contrary to all expectation, some genes were actively making RNA transcripts. These turned out to be silencing RNA genes. "That suggests that in order to silence DNA it has to be transcribed first," he said. Dr. Martienssen and others reported evidence that the RNA transcripts from the silencing genes seem to stay in place on the DNA and recruit enzymes that are known to set switches on the chromatin, turning it into the closed form. Thus, the location of the RNA genes in the strands of DNA seems to help determine what regions will be marked for silencing. So many questions about regulatory RNA's have arisen that Gary Ruvkun of M.I.T., who discovered one of the first RNA genes, announced a list of 23 problems, reflecting the list of 23 outstanding mathematical problems posed by David Hilbert in 1900. Dr. Ruvkun described the puzzles raised by regulatory RNA to the symposium but stopped at No. 18 — whether to leave time for the rest of his talk or, as he explained, "Out of modesty." One scientist at the conference, James D. Watson, the co-discoverer of the structure of DNA, said, "This is a revolution." "Source":[ http://www.nytimes.com/2006/06/20/science/20RNA.html]

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