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Jamming the ratchet of transcription

Nature Structural & Molecular Biology volume 15, pages 777–779 (2008)Cite this article

The exact mechanism by which cellular RNA polymerases translocate and maintain exceptionally high fidelity during transcription remains an important unresolved issue. Two recent structural studies of yeast RNA polymerase II in complex with its potent inhibitor, the fungal toxin α-amanitin, address this matter by describing crucial and surprising details about the dynamic organization of the enzyme catalytic center.

Eukaryotic protein-coding genes are transcribed by a dedicated class of DNA-dependent RNA polymerases (RNAPs), so-called RNA polymerase II (Pol II). This enzyme is exceptionally processive and faithful, synthesizing RNA molecules thousands of nucleotides long without a single mistake. Although many details of transcription mechanisms have already been revealed by structural, biochemical and biophysical studies of Pol II and related bacterial enzymes1, some fundamental issues, such as the driving forces and fidelity of RNAP, remain to be elucidated. RNA synthesis occurs by simple two-metal catalysis facilitated by an absolutely conserved triad of acidic amino acids grouped together within a short peptide loop in the catalytic center of RNAP. Yet, remarkably, RNAP is comprised of several—in the case of yeast Pol II, twelve—subunits and thousands of amino acids, and it shows profound allosteric effects propagated over large distances. Two recent papers from the Kornberg and Cramer laboratories2,3 provide, in many aspects, complementary insights into the structural and mechanochemical bases of Pol II function and the mechanism of its inhibition by the powerful fungal toxin α-amanitin.

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Figure 1: Structural elements of yeast Pol II crucial for α-amanitin action.
Figure 2: Model of RNA polymerase nucleotide addition cycle (NAC).

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Acknowledgements

This work was supported by grants from the US National Institutes of Health.

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  1. Vladimir Svetlov and Evgeny Nudler are in the Department of Biochemistry, New York University School of Medicine, New York, New York 10016, USA. evgeny.nudler@nyumc.org

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  1. Vladimir Svetlov
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  2. Evgeny Nudler
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Svetlov, V., Nudler, E. Jamming the ratchet of transcription. Nat Struct Mol Biol 15, 777–779 (2008). https://doi.org/10.1038/nsmb0808-777

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