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Mutations in several ribosomal proteins (RPs) lead to Diamond-Blackfan anemia (DBA), a syndrome characterized by defective erythropoiesis, congenital anomalies, and increased frequency of cancer. RPS19 is the most frequently mutated RP in DBA. RPS19 deficiency impairs ribosomal biogenesis, but how this leads to DBA or cancer remains unknown. We have found that rps19 deficiency in zebrafish results in hematopoietic and developmental abnormalities resembling DBA. Our data suggest that the rps19-deficient phenotype is mediated by dysregulation of deltaNp63 and p53. During gastrulation, deltaNp63 is required for specification of nonneural ectoderm and its up-regulation suppresses neural differentiation, thus contributing to brain/ craniofacial defects. In rps19-deficient embryos, deltaNp63 is induced in erythroid progenitors and may contribute to blood defects. We have shown that suppression of p53 and deltaNp63 alleviates the rps19-deficient phenotypes. Mutations in other ribosomal proteins, such as S8, S11, and S18, also lead to up-regulation of p53 pathway, suggesting it is a common response to ribosomal protein deficiency. Our finding provides new insights into pathogenesis of DBA. Ribosomal stress syndromes represent a broader spectrum of human congenital diseases caused by genotoxic stress; therefore, imbalance of p53 family members may become a new target for therapeutics. (Blood. 2008;112: 5228-5237) IntroductionThe precise control of ribosome biogenesis and translation is vital for cell survival. Cell growth and proliferation as well as responses to genotoxic stress depend on ribosomal activity. Defective ribosomal synthesis has been associated with bone marrow failure syndromes, such as Diamond-Blackfan anemia (DBA), dyskeratosis congenita, and Shwachman-BodianDiamond syndrome. 1 DBA is a congenital syndrome characterized by anemia, bone marrow erythroblastopenia, and increased incidence of cancer. [1][2][3] Anemia is often accompanied by growth retardation and various malformations. Ribosomal protein S19 (RPS19) is mutated in one fourth of patients 4 ; mutations of other ribosomal proteins can also lead to DBA. 5,6 Red blood cells of DBA patients manifest altered transcription, translation, and activated apoptotic pathways. 7-9 RPS19 is necessary for ribosome biosynthesis. Certain RPS19 mutations affect its structure and assembly into the ribosome. 10,11 In yeast and human, deficiency of RPS19 impairs the processing of 18S rRNA and aberrant pre-40S particles are retained in the nucleolus. [12][13][14] Nucleolar organization is distorted in skin fibroblasts in all DBA patients regardless of the presence of RPS19 mutations, 13 suggesting that defect in ribosome biogenesis is a general feature of DBA. The nucleolus can act as a stress sensor; its disruption mediated p53 up-regulation. 15 Mutations in other proteins participating in ribosome biogenesis lead to p53 up-regulation. [16][17][18] Haploinsufficiency of RPS6 and RPL22 also leads to activation of p53. 19,20 Hence, we hypothesized that up-regulation o...

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Defects in ribosome biogenesis are associated with a group of diseases called the ribosomopathies, of which Diamond-Blackfan anemia (DBA) is the most studied. Ribosomes are composed of ribosomal proteins (RPs) and ribosomal RNA (rRNA). RPs and multiple other factors are necessary for the processing of pre-rRNA, the assembly of ribosomal subunits, their export to the cytoplasm and for the final assembly of subunits into a ribosome. Haploinsufficiency of certain RPs causes DBA, whereas mutations in other factors cause various other ribosomopathies. Despite the general nature of their underlying defects, the clinical manifestations of ribosomopathies differ. In DBA, for example, red blood cell pathology is especially evident. In addition, individuals with DBA often have malformations of limbs, the face and various organs, and also have an increased risk of cancer. Common features shared among human DBA and animal models have emerged, such as small body size, eye defects, duplication or overgrowth of ectoderm-derived structures, and hematopoietic defects. Phenotypes of ribosomopathies are mediated both by p53-dependent and -independent pathways. The current challenge is to identify differences in response to ribosomal stress that lead to specific tissue defects in various ribosomopathies. Here, we review recent findings in this field, with a particular focus on animal models, and discuss how, in some cases, the different phenotypes of ribosomopathies might arise from differences in the spatiotemporal expression of the affected genes.

Summary Mutations in ribosomal proteins are associated with a congenital syndrome, Diamond–Blackfan anaemia (DBA), manifested by red blood cell aplasia, developmental abnormalities and increased risk of malignancy. Recent studies suggest the involvement of p53 activation in DBA. However, which pathways are involved and how they contribute to the DBA phenotype remains unknown. Here we show that a zebrafish mutant for the rpl11 gene had defects both in the development of haematopoietic stem cells (HSCs) and maintenance of erythroid cells. The molecular signature of the mutant included upregulation of p53 target genes and global changes in metabolism. The changes in several pathways may affect haematopoiesis including upregulation of pro-apoptotic and cell cycle arrest genes, suppression of glycolysis, downregulation of biosynthesis and dysregulation of cytoskeleton. Each of these pathways has been individually implicated in haematological diseases. Inhibition of p53 partially rescued haematopoiesis in the mutant. Altogether, we propose that the unique phenotype of DBA is a sum of several abnormally regulated molecular pathways, mediated by the p53 protein family and p53-independent, which have synergistic impact on haematological and other cellular pathways affected in DBA. Our results provide new insights into the pathogenesis of DBA and point to the potential avenues for therapeutic intervention.