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J. Biol. Chem., Vol. 283, Issue 38, 26026-26036, September 19, 2008

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Ribosome Performance Is Enhanced by a Rich Cluster of Pseudouridines in the A-site Finger Region of the Large Subunit^*

Dorota Piekna-Przybylska¹, Piotr Przybylski, Agnès Baudin-Baillieu, Jean-Pierre Rousset, and Maurille J. Fournier²

From the Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, Massachusetts 01003 and the Institute of Genetics and Microbiology, Université Paris-Sud, UMR 8621, Orsay F91405, France

The large subunit rRNA in eukaryotes contains an unusually dense cluster of 8–10 pseudouridine () modifications located in a three-helix structure (H37–H39) implicated in several functions. This region is dominated by a long flexible helix (H38) known as the "A-site finger" (ASF). The ASF protrudes from the large subunit just above the A-site of tRNA binding, interacts with 5 S rRNA and tRNA, and through the terminal loop, forms a bridge (B1a) with the small subunit. In yeast, the three-helix domain contains 10 s and 6 are concentrated in the ASF helix (3 of the ASF s are conserved among eukaryotes). Here, we show by genetic depletion analysis that the s in the ASF helix and adjoining helices are not crucial for cell viability; however, their presence notably enhances ribosome fitness. Depleting different combinations of s suggest that the modification pattern is important and revealed that loss of multiple s negatively influences ribosome performance. The effects observed include slower cell growth (reduced rates up to 23% at 30 °C and 40–50% at 37 °C and 11 °C), reduced level of the large subunit (up to 17%), impaired polysome formation (appearance of half-mers), reduced translation activity (up to 20% at 30 °C and 25% at 11 °C), and increased sensitivity to ribosome-based drugs. The results indicate that the s in the three-helix region improve fitness of a eukaryotic ribosome.

Received for publication, April 21, 2008 , and in revised form, July 7, 2008.

^* This work was supported by United States Public Health Services Grant GM19351 (to M. J. F.) and by Association Française contre les Myopathies Grant 12652 and Association pour la Recherche sur le Cancer Grant 3849 (to J. P. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1, Figs. S1–S4, text, and references.

¹ Present address: Dept. of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.

² To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Lederle Graduate Research Tower, University of Massachusetts, Amherst, MA 01003. Tel.: 413-545-2732; Fax: 413-545-3291; E-mail: 4nier{at}biochem.umass.edu.

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