Diamond Blackfan Anemia: Ribosomal Proteins Going Rogue

Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY 40292, USA.
Seminars in Hematology (Impact Factor: 3.27). 04/2011; 48(2):89-96. DOI: 10.1053/j.seminhematol.2011.02.005
Source: PubMed


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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Available from: Pierre-Emmanuel Gleizes, Jul 30, 2015
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    • "Whereas a complete genetic ablation of individual r-proteins leads to severe growth defects and organismal lethality, with only a few known exceptions (Kirn-Safran et al. 2007; McIntosh et al. 2011; Babiano et al. 2012; Steffen et al. 2012; O'Leary et al. 2013), their suboptimal expression often results in complex pathological phenotypes. In humans, reduced expression or partial loss of function in a number of r-proteins are associated with a group of congenital disorders termed ribosomopathies, characterized by impaired proliferation and increased cell death in hematopoietic progenitors and certain other cell lineages (Ellis and Gleizes 2011; Raiser et al. 2014). On a subcellular level, defects in ribosome biogenesis lead to reduced protein synthesis capacity and misregulated translational controls (Horos et al. 2012; Teng et al. 2013; Ludwig et al. 2014). "
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    ABSTRACT: Processing of rRNA during ribosome assembly can proceed through alternative pathways but it is unclear whether this could affect the structure of the ribosome. Here, we demonstrate that shortage of a ribosomal protein can change pre-rRNA processing in a way that over time alters ribosome diversity in the cell. Reducing the amount of Rpl17 in mouse cells led to stalled 60S subunit maturation, causing degradation of most of the synthesized precursors. A fraction of pre-60S subunits, however, were able to complete maturation, but with a 5'-truncated 5.8S rRNA, which we named 5.8SC. The 5' exoribonuclease Xrn2 is involved in the generation of both 5.8SC and the canonical long form of 5.8S rRNA. Ribosomes containing 5.8SC rRNA are present in various mouse and human cells and engage in translation. These findings uncover a previously undescribed form of mammalian 5.8S rRNA and demonstrate that perturbations in ribosome assembly can be a source of heterogeneity in mature ribosomes. © 2015 Wang et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.
    RNA 05/2015; 21(7). DOI:10.1261/rna.051169.115 · 4.94 Impact Factor
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    • "Haploinsufficiency for ribosomal proteins is believed to lead to the failure of red cell production due to apoptosis [14], [15] and/or decreased proliferation due to cell cycle arrest of erythroid progenitors [16]. In addition, haploinsufficiency of ribosomal proteins decreases the efficiency of ribosome assembly triggering nucleolar stress [17] resulting in enhanced translation of other ribosomal protein mRNAs (5′-terminal oligopyrimidine tract [5′-TOP] containing mRNAs) [18]. Ribosomal proteins such as RPL11, RPL5, RPL23, RPS7 and RPS3 [19]–[22] have been previously suggested to bind to and inhibit the activity of an E3 ubiquitin ligase, HDM2 (MDM2 in mice) in contexts of nucleolar stress. "
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    ABSTRACT: Diamond Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome caused by ribosomal protein haploinsufficiency. DBA exhibits marked phenotypic variability, commonly presenting with erythroid hypoplasia, less consistently with non-erythroid features. The p53 pathway, activated by abortive ribosome assembly, is hypothesized to contribute to the erythroid failure of DBA. We studied murine embryonic stem (ES) cell lines harboring a gene trap mutation in a ribosomal protein gene, either Rps19 or Rpl5. Both mutants exhibited ribosomal protein haploinsufficiency and polysome defects. Rps19 mutant ES cells showed significant increase in p53 protein expression, however, there was no similar increase in the Rpl5 mutant cells. Embryoid body formation was diminished in both mutants but nonspecifically rescued by knockdown of p53. When embryoid bodies were further differentiated to primitive erythroid colonies, both mutants exhibited a marked reduction in colony formation, which was again nonspecifically rescued by p53 inhibition. Cell cycle analyses were normal in Rps19 mutant ES cells, but there was a significant delay in the G2/M phase in the Rpl5 mutant cells, which was unaffected by p53 knockdown. Concordantly, Rpl5 mutant ES cells had a more pronounced growth defect in liquid culture compared to the Rps19 mutant cells. We conclude that the defects in our RPS19 and RPL5 haploinsufficient mouse ES cells are not adequately explained by p53 stabilization, as p53 knockdown appears to increase the growth and differentiation potential of both parental and mutant cells. Our studies demonstrate that gene trap mouse ES cells are useful tools to study the pathogenesis of DBA.
    PLoS ONE 02/2014; 9(2):e89098. DOI:10.1371/journal.pone.0089098 · 3.23 Impact Factor
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    • "Their studies reveal that extraribosomal levels of Rpl11 increase through translational upregulation or via abortive assembly depending on whether the 40S or 60S subunit is affected, respectively. The concept of rogue ribosomal proteins regulating HDM2/MDM2 as a means for upregulation of p53 in response to abortive ribosome assembly provides an appealing model for the underlying molecular basis of DBA [25]. "
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    ABSTRACT: Diamond Blackfan anemia is a red cell hypoplasia that typically presents within the first year of life. Most cases of Diamond Blackfan anemia are caused by ribosome assembly defects linked to haploinsufficiency for structural proteins of either ribosomal subunit. Nucleolar stress associated with abortive ribosome assembly leads to p53 activation via the interaction of free ribosomal proteins with HDM2, a negative regulator of p53. Significant challenges remain in linking this nucleolar stress signaling pathway to the clinical features of Diamond Blackfan anemia. Defining aspects of disease presentation may relate to developmental and physiological triggers that work in conjunction with nucleolar stress signaling to heighten the p53 response in the developing erythron after birth. The growing number of ribosomopathies provides additional challenges for linking molecular mechanisms with clinical phenotypes. This article is part of a Special Issue entitled: Role of the Nucleolus in Human Disease.
    Biochimica et Biophysica Acta 01/2014; 1842(6). DOI:10.1016/j.bbadis.2013.12.013 · 4.66 Impact Factor
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