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Breakthrough of the Year: Small RNAs

19 December 2002 (All day)
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Life cycle. With a helping hand from proteins RISC and DICER (scissors), small RNAs are born. We now know that these molecules keep DNA in line and ensure a cell's good health.

For decades, RNA molecules were dismissed as little more than drones, taking orders from DNA and converting genetic information into proteins. But a string of recent discoveries indicates that a class of RNA molecules called small RNAs are actually in charge of many cellular functions. Science hails these discoveries, which are prompting biologists to overhaul their vision of the cell and its evolution, as 2002's Breakthrough of the Year.

The role of short stretches of RNA, which range in length from 21 to 28 nucleotides, had gone unnoticed until recently, in part because researchers, focused on the familiar larger RNA molecules, tossed out the crucial small ones during experiments. Then in 1998, researchers found that injecting a type of RNA, called double-stranded RNA, in worms dramatically inhibited certain genes. This inhibition, which was later seen in flies and other organisms, came to be known as RNA interference (RNAi). Biologists have come to believe that RNAi protects against harmful DNA or viruses that could disrupt the genome.

The year's most stunning revelations emerged in the fall, in four papers examining how RNA interference helps pilot a peculiar--and pervasive--genetic phenomenon known as epigenetics. Epigenetics refers to changes in gene expression that persist across at least one generation but are not caused by changes in the DNA code. One type of epigenetic regulation is caused by changes to the shape of complexes called chromatin, the bundles of DNA and certain fundamental proteins that make up the chromosomes. By changing shape--becoming either more or less compact--chromatin can alter which genes are expressed.

This year, scientists peering closely at RNAi in two different organisms were startled to find that small RNAs responsible for RNAi wield tremendous control over the shape of chromatin. In so doing, they can permanently shut down or delete sections of DNA (by mechanisms not well understood), rather than just silencing them temporarily.

That news came from several independent groups. In one case, Shiv Grewal, Robert Martienssen, and their colleagues at Cold Spring Harbor Laboratory found that fission yeast cells that lacked the usual small RNAs couldn't properly form a type of chromatin at certain locations in the genome. The scientists theorized that in healthy yeast cells, small RNAs somehow nudge this material into the right position. That exposes DNA to different proteins, thereby dampening gene expression; in this particular case, that disrupts proper cell division.

Meanwhile, other groups, such as David Allis and his colleagues at the University of Virginia Health System in Charlottesville and Martin Gorovsky at the University of Rochester in New York and others, discovered that small RNAs trigger deletion or reshuffling of some DNA sequences during the division of a single-celled ciliate called Tetrahymena.

The yeast and Tetrahymena experiments might help explain why small RNAs exist in the first place. In both, small RNAs' frenetic activity is focused on genome regions that contain repetitive DNA. This DNA, called transposons, can jump around the genome and insert themselves at different locales; at times they jam transcription machinery and cause disease. It appears possible--although still largely hypothetical--that small RNAs evolved very early in evolution to help protect the genome against instability.

This is just one of many areas that remain to be explored. Researchers are still trying to sort out how the well over 100 small RNAs function. RNAi has been implicated in guiding the plant version of stem cells, so some biologists believe that it might help clarify the differentiation of mammalian stem cells. If so, RNAi could prove an essential tool in manipulating stem cells. And if small RNAs influence cell division in humans as they do in yeast and Tetrahymena, minor disruptions in the machinery could lead to cancer.

Related sites
More detailed Science article on the Breakthrough of the Year
Grewal laboratory
Martienssen laboratory
Gorovsky laboratory
Allis laboratory

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