Diamond Blackfan anemia: ribosomal proteins going rogue.
ABSTRACT Within the decade following the demonstration that mutations in the RPS19 gene can lead to Diamond-Blackfan anemia (DBA), this disease has become a paradigm for an emerging group of pathologies linked to defects in ribosome biogenesis. DBA patients exhibit abnormal pre-rRNA maturation patterns and the majority bear mutations in one of several ribosomal protein genes that encode structural components of the ribosome essential for the correct assembly of the ribosomal subunits. Extensive study of the most frequently mutated gene, RPS19, has shown that mutations prevent the assembly of the ribosomal protein into forming pre-ribosomal particles. This defect in ribosome production triggers nucleolar stress pathways, the activation of which appears to be central to pathophysiological mechanisms. Why mutations in ribosomal protein genes so strongly and specifically affect erythropoiesis in DBA remains a challenging question, especially given the fact that defects in genes encoding nonstructural ribosome biogenesis factors have been shown to cause diseases other than DBA. A major problem in understanding the pathophysiological mechanisms in DBA remains the lack of a suitable animal model. Despite this, considerable strides have been made over that past few years demonstrating that several factors involved in the synthesis of ribosomes are targets of disease-causing mutations.
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ABSTRACT: eLife digest The production of a protein in a cell starts with a region of DNA being transcribed to produce a molecule of messenger RNA. A large molecular machine called ribosome then reads the information in the messenger RNA molecule to produce a protein. Ribosomes themselves are made of RNA and several different proteins called r-proteins. The construction of a ribosome starts with the assembly of a pre-ribosome inside the cell nucleus, and the ribosome is completed in the cytosol of the cell. A yeast cell will divide about 30 times during its lifetime, and before each division event a single yeast cell needs to import about 14 million r-proteins into its nucleus in order to make about 200,000 ribosomes. However, many details of this process are mysterious. In particular, many r-proteins are known to be unstable: meaning that, left to their own devices, r-proteins are highly likely to aggregate, which would prevent them becoming part of a ribosome. Now, Schütz et al. have figured out how a carrier protein called Tsr2 makes sure that an r-protein called eS26 does indeed become part of a ribosome. The human disorder known as Diamond-Blackfan anemia is caused by a mutation in the gene for eS26. The eS26 proteins are ferried to the cell nucleus on specialized transport vehicles. Schütz et al. have now shown that the Tsr2 carrier protein unloads the r-protein from the transport vehicle in the nucleus, and then binds it. This means that the r-protein does not form an aggregate. Finally, the Tsr2 carrier protein transfers the r-protein to the pre-ribosome. This is the first time that a carrier protein that unloads an r-protein cargo from its transport vehicle, to ensure safe delivery to the pre-ribosome, has been identified. DOI: http://dx.doi.org/10.7554/eLife.03473.002eLife Sciences 08/2014; 3:e03473. DOI:10.7554/eLife.03473 · 8.52 Impact Factor
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ABSTRACT: Defects in genes encoding ribosomal proteins cause Diamond Blackfan Anemia (DBA), a red cell aplasia often associated with physical abnormalities. Other bone marrow failure syndromes have been attributed to defects in ribosomal components but the link between erythropoiesis and the ribosome remains to be fully defined. Several lines of evidence suggest that defects in ribosome synthesis lead to “ribosomal stress” with p53 activation and either cell cycle arrest or induction of apoptosis. Pathways independent of p53 have also been proposed to play a role in DBA pathogenesis. We took an unbiased approach to identify p53-independent pathways activated by defects in ribosome synthesis by analyzing global gene expression in various cellular models of DBA. Ranking-Principal Component Analysis (Ranking-PCA) was applied to the identified datasets to determine whether there are common sets of genes whose expression is altered in these different cellular models. We observed consistent changes in the expression of genes involved in cellular amino acid metabolic process, negative regulation of cell proliferation and cell redox homeostasis. These data indicate that cells respond to defects in ribosome synthesis by changing the level of expression of a limited subset of genes involved in critical cellular processes. Moreover, our data support a role for p53-independent pathways in the pathophysiology of DBA.Gene 07/2014; 545(2):282–289. · 2.08 Impact Factor
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ABSTRACT: Ribosomal RNAs are the most abundant and universal noncoding RNAs in living organisms. In eukaryotes, three of the four ribosomal RNAs forming the 40S and 60S subunits are borne by a long polycistronic pre-ribosomal RNA. A complex sequence of processing steps is required to gradually release the mature RNAs from this precursor, concomitant with the assembly of the 79 ribosomal proteins. A large set of trans-acting factors chaperone this process, including small nucleolar ribonucleoparticles. While yeast has been the gold standard for studying the molecular basis of this process, recent technical advances have allowed to further define the mechanisms of ribosome biogenesis in animals and plants. This renewed interest for a long-lasting question has been fueled by the association of several genetic diseases with mutations in genes encoding both ribosomal proteins and ribosome biogenesis factors, and by the perspective of new anticancer treatments targeting the mechanisms of ribosome synthesis. A consensus scheme of pre-ribosomal RNA maturation is emerging from studies in various kinds of eukaryotic organisms. However, major differences between mammalian and yeast pre-ribosomal RNA processing have recently come to light.For further resources related to this article, please visit the WIREs website.Conflict of interest: The authors have declared no conflicts of interest for this article.WIREs RNA 10/2014; DOI:10.1002/wrna.1269 · 6.15 Impact Factor