Defects in ribosome biogenesis are associated with a group of diseases

Defects in ribosome biogenesis are associated with a group of diseases called the ribosomopathies, of which Diamond-Blackfan anemia (DBA) is the most studied. 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 GR-203040 genes. mutations accounting for about 25% of all cases GR-203040 (Table 1). Although some mutations are dominant negative, the major mechanism of the disease is associated with haploinsufficiency of an RP that disrupts the processing of pre-ribosomal RNA (pre-rRNA), leading to abortive ribosome biogenesis (Choesmel et al., 2007; Devlin et al., 2010; Farrar et al., 2014; Flygare et al., 2007; Gazda et al., 2004; Leger-Silvestre et al., 2005; Panic et al., 2006). Box 1. Glossary 5 and 3 external transcribed spacers (ETSs): non-functional RNA sequences of the pre-rRNA transcript that have structural roles and are excised during pre-rRNA processing. 5q-myelodysplastic syndrome (5q-MDS): a form of MDS that is caused by loss of a part of the q arm of chromosome 5. Adenosine deaminase (ADA): an enzyme involved in the metabolism of adenosine. Anemia: a condition associated with an insufficient number of red blood cells in blood. Asplenia: absence of spleen or very small spleen. Biliary cirrhosis: cirrhosis caused by damage to the bile ducts in the liver. Epiboly: growth of a cell layer to envelope the yolk during gastrulation. Haploinsufficiency: when a single copy of the gene is insufficient to maintain normal function. Internal ribosome entry site (IRES): a sequence inside mRNA that allows for initiation of cap-independent translation in the middle of mRNA. Internally transcribed spacers (ITSs): spacers between 18S, 5.8S and 28S rRNA in the pre-rRNA transcript that play structural roles and, like ETSs, are excised during pre-rRNA processing. Jaundice: yellow color of the skin and whites of the eyes caused by excess bilirubin in the blood. Macrocytic erythrocytes: abnormally large red blood cells. Mechanistic target of rapamycin (mTOR): a serine/threonine kinase that is a central regulator of cellular metabolism. It forms mTORC1 and mTORC2 complexes, which mediate cellular responses to stresses such as DNA damage and nutrient deprivation. Myelodysplastic syndrome (MDS): a syndrome caused by mutations in several genes, most often encoding splicing factors. It is associated with ineffective production of blood, which often leads to leukemia. Reticulocyte: immature erythrocyte. RNA polymerase I and Rabbit polyclonal to SR B1 III (PolI/PolIII): enzymes involved in the transcription of non-coding RNAs. Ribosomal proteins (RPs): proteins that together with ribosomal RNA (rRNA) make up the ribosome. They are called RPS (RP from small ribosomal subunit) or RPL (RP from large ribosomal subunit) depending on whether they associate with the small or large subunit of the ribosome. Small nucleolar RNA (snoRNA): a class of small RNAs that guide chemical modifications such as methylation and pseudouridylation of other RNAs. Table 1. Genes mutated in DBA DBA is a rare disease with an incidence of 5 cases per million live births, but it has attracted substantial attention as a model disease for ribosomopathies, a group of pathologies associated with defects in ribosome biogenesis (Armistead and Triggs-Raine, 2014; James et al., 2014). Despite this common defect, phenotypes of ribosomopathies differ. A common feature among several ribosomopathies is p53 activation (Danilova et al., 2008b; Elghetany and Alter, 2002; Jones et al., 2008), but the mechanisms involved have not been completely elucidated. A p53-independent response to RP deficiency has also been observed (Aspesi et al., 2014; Danilova et al., 2008b; Singh et al., 2014; Torihara et al., 2011). The pathways that lead from a particular defect in ribosome biogenesis to the phenotype of a ribosomopathy are still not well understood. Several insightful reviews about the mechanisms of ribosomopathies have been published recently (Armistead and Triggs-Raine, 2014; Ellis, 2014; Golomb et al., 2014; James et al., 2014; Ruggero and Shimamura, 2014) with a focus on human data. However, cross-species analysis might also provide additional clues as to the mechanisms of these diseases. Here, we review the phenotypes that are caused by RP deficiency in humans as well as in mouse, fly and zebrafish models, with an emphasis on their common features. We also discuss the consequences of ribosomal stress at the molecular level, with a particular emphasis on p53 activation, metabolic changes, the origin of erythroid defects, and congenital malformations. We also GR-203040 discuss potential new directions for.