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J. Biol. Chem., Vol. 280, Issue 46, 38177-38185, November 18, 2005

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Specific Role for Yeast Homologs of the Diamond Blackfan Anemia-associated Rps19 Protein in Ribosome Synthesis^*

Isabelle Léger-Silvestre, Jacqueline Marie Caffrey1, Rosy Dawaliby1, Diana Alehandrovna Alvarez-Arias¶, Nicole Gas2, Salvatore J. Bertolone||, Pierre-Emmanuel Gleizes23, and Steven Robert Ellis¶4

From the Laboratoire de Biologie Moléculaire des Eucaryotes (UMR5099) and Institut d'Exploration Fonctionnelle des Génomes (IFR109), CNRS and Université Paul Sabatier, 118 route de Narbonne, 31062 Toulouse, France and the Departments of Biochemistry and Molecular Biology, ^¶Chemistry, and ^||Pediatrics, University of Louisville, Louisville, Kentucky 40292

Approximately 25% of cases of Diamond Blackfan anemia, a severe hypoplastic anemia, are linked to heterozygous mutations in the gene encoding ribosomal protein S19 that result in haploinsufficiency for this protein. Here we show that deletion of either of the two genes encoding Rps19 in yeast severely affects the production of 40 S ribosomal subunits. Rps19 is an essential protein that is strictly required for maturation of the 3'-end of 18 S rRNA. Depletion of Rps19 results in the accumulation of aberrant pre-40 S particles retained in the nucleus that fail to associate with pre-ribosomal factors involved in late maturation steps, including Enp1, Tsr1, and Rio2. When introduced in yeast Rps19, amino acid substitutions found in Diamond Blackfan anemia patients induce defects in the processing of the pre-rRNA similar to those observed in cells under-expressing Rps19. These results uncover a pivotal role of Rps19 in the assembly and maturation of the pre-40 S particles and demonstrate for the first time the effect of Diamond Blackfan anemia-associated mutations on the function of Rps19, strongly connecting the pathology to ribosome biogenesis.

Received for publication, June 24, 2005 , and in revised form, August 8, 2005.

^* This work was supported in part by grants from the Kentucky Lung Cancer Research Program and NHLBI, National Institutes of Health (to S. R. E.). 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.

¹ Both authors contributed equally to this work.

² Received funds from the CNRS, the French Ministry of Research (Actions Concertées Incitatives Microbiologie) and the Association pour la Recherche contre le Cancer (Paris, France).

³ To whom correspondence may be addressed. Tel.: 33-561-335-926; Fax: 33-561-335-886; E-mail: gleizes{at}ibcg.biotoul.fr. ⁴ To whom correspondence may be addressed. Tel.: 502-852-5222; Fax: 502-852-6222; E-mail: srellis{at}louisville.edu.

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