Human Molecular Genetics Advance Access published online on January 29, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn015
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Mutation of ribosomal protein RPS24 in Diamond-Blackfan anemia results in a ribosome biogenesis disorder
1 Université de Toulouse, Laboratoire de Biologie Moléculaire Eucaryote, 31062 Toulouse, France 2 CNRS, UMR 5599, 31062 Toulouse, France 3 INSERM U869, Institut Européen de Chimie et Biologie, F-33607, France. 4 Université Victor Segalen, Bordeaux 2, F-33076, France. 5 Synchrotron SOLEIL, 91192 Gif sur Yvette Cedex, France. 6 Children's Hospital Boston, Division of Genetics and Program in Genomics, Boston, MA, USA 7 Harvard Medical School, Boston, MA, USA
* Correspondence to: Pierre-Emmanuel Gleizes, LBME-CNRS, 118 route de Narbonne, F- 31062 Toulouse cedex, Phone: +33-561 335 926Fax: +33-561 335 886 gleizes{at}ibcg.biotoul.fr
Received November 12, 2007; Revised January 10, 2008; Accepted January 16, 2008
Diamond-Blackfan anemia (DBA) is a rare congenital disease affecting erythroid precursor differentiation. Remarkably, DBA is emerging as a paradigm for a new class of pathologies potentially linked to disorders in ribosome biogenesis. Three genes encoding ribosomal proteins have been associated to DBA: after RPS19, mutations in genes RPS24 and RPS17 were recently identified in a fraction of the patients. Here we show that cells from patients carrying mutations in RPS24 have defective pre-rRNA maturation, as in the case of RPS19 mutations. However, in contrast with RPS19 involvement in maturation of the internal transcribed spacer 1, RPS24 is required for processing of the 5 external transcribed spacer (5-ETS). Remarkably, epistasis experiments with siRNAs indicate that the functions of RPS19 and RPS24 in pre-rRNA processing are connected. Resolution of the crystal structure of RPS24e from the archeon Pyroccocus abyssi reveals domains of RPS24 potentially involved in interactions with pre-ribosomes. Based on these data, we discuss the impact of RPS24 mutations and speculate that RPS19 and RPS24 cooperate at a particular stage of ribosome biogenesis connected to a cell cycle checkpoint, thus affecting differentiation of erythroid precursors as well as developmental processes.
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