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Nobel Laureate finds 'elegant' explanation for DNA transcribing enzyme's high fidelity

Last month, Roger Kornberg of Stanford University won the Nobel Prize in Chemistry for his efforts to unravel the molecular basis of eukaryotic transcription, in which enzymes give voice to DNA by copying it into the RNA molecules that serve as templates for protein in organisms from yeast to humans. Now, Kornberg and his colleagues report in the December 1, 2006 issue of the journal Cell, published by Cell Press, new structures that reveal another critical piece of the puzzle: how the so-called polymerase II enzyme discriminates among potential RNA building blocks to ensure the characteristic accuracy of the process.

The researchers found that a portion of the enzyme known as the trigger loop acts like a trap door, swinging beneath a matching nucleoside triphosphate (NTP) building block, to close off the active center and form an extensive network of interactions with the NTP and other parts of the enzyme. Those interactions leave another side chain in the trigger loop precisely positioned, such that it may literally trigger the formation of the chemical bonds that link components of the growing RNA chain together. If the NTP is even slightly misaligned, Kornberg said, those critical interactions fail.

The trigger loop mechanism therefore couples NTP recognition and catalysis, ensuring the fidelity of transcription, they reported.

Of all revelations from the structure [of the transcription machinery] since it was first solved, this is perhaps the most fundamental since it gets at the underlying mechanisms, Kornberg said. Its long known that the enzyme operates with high fidelityselecting the correct base and sugarbut its been a mystery how that is accomplished.

These findings offer an unexpected and elegant explanation thats both beautiful and simple, as nature invariably proves to be.

The fundamental mechanism of transcription is conserved among cellular RNA polymerases, the researchers explained. Common features in
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Contact: Heidi Hardman
hhardman@cell.com
617-397-2879
Cell Press
30-Nov-2006


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