Ribosomes and marrow failure: coincidental association or molecular paradigm?

Abstract

IntroductionInherited bone marrow failure syndromes including dyskeratosis congenita (DC), cartilage-hair hypoplasia (CHH), DiamondBlackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS) have long fascinated and challenged geneticists and hematologists. This heterogeneous group of disorders is characterized by bone marrow failure and the variable presence of congenital anomalies and cancer predisposition (Table 1). While there has been rapid progress in identifying gene defects in nearly all the disorders, understanding the molecular pathophysiology has lagged behind in most instances. Intriguingly, genes mutated in many of these disorders encode factors involved in ribosome synthesis, suggesting a link between this fundamental cellular process and marrow failure. In this "Perspective," we wish to define this association and critically assess its validity in the light of new research.Broadly speaking, the genes mutated in the inherited marrow failure syndromes (reviewed in J. M. Lipton, J.M.L., and A. Vlachos, manuscript submitted) have widely disparate functions (Fanconi anemia genes, GFI1, ELA2, RUNX1, HOXA11, GATA1, and others) without an obvious molecular interrelationship. By contrast, genes mutated in X-linked DC, 1 CHH, 2 DBA, 3 and SDS 4 are all predicted to be involved in aspects of ribosome synthesis. Complicating this picture, however, is the fact that some of the factors encoded by these genes are multifunctional, influencing one or more critical cellular processes in addition to ribosome synthesis. The most extensively studied bone marrow failure syndrome from this perspective is X-linked DC, which is caused by mutations in DKC1 (its encoded protein also known as dyskerin). 1 Dyskerin is a putative pseudouridyl synthase found in so-called H/ACA ribonucleoprotein complexes involved in ribosomal RNA (rRNA) modification. Since its discovery, dyskerin has also been shown to be a component of other ribonucleoprotein complexes including telomerase. 5 A similarly complex picture is emerging for CHH. The gene affected in CHH is RMRP, which encodes the RNA component of ribonuclease mitochondrial RNA processing (RNase MRP). 2 RNase MRP is a multifunctional ribonucleoprotein complex involved in cleaving rRNA precursors, processing of RNA primers used in mitochondrial DNA replication, and the turnover of certain cell cycle-regulated mRNAs. The only gene linked to DBA to date encodes ribosomal protein S19 (RPS19), 3 which in yeast is required for the maturation of 40S ribosomal subunits. 6 Here again, the human RPS19 protein has been proposed to have a function outside of this role. 7 Finally, several studies have suggested that SBDS, mutations in which cause SDS, 4 encodes a protein involved in ribosome synthesis. 8,9 Thus, although defective ribosome synthesis may contribute to each of the bone marrow failure syndromes under discussion here, precisely which feature, if any, of each disease is a consequence of failure to produce adequate amounts of ribosomes is obscured by the tendency of each gene produc...

Ribosomopathies: human disorders of ribosome dysfunction

“…Moreover, other congenital syndromes have been linked to defective ribosome biogenesis, including Schwachman-Diamond syndrome (SDS), X-linked dyskeratosis congenita (DKC), cartilage hair hypoplasia (CHH), and Treacher Collins syndrome (TCS). 2 In the 5qϪ syndrome, a subtype of adult myelodysplastic syndrome, acquired haploinsufficiency for RPS14 resulting from an interstitial chromosomal deletion causes a severe refractory anemia. 3 Each of these disorders is associated with specific defects in ribosome biogenesis, which cause distinct clinical phenotypes, most often involving bone marrow failure and/or craniofacial or other skeletal defects.…”

“…Haploinsufficiencies for distinct ribosomal proteins have been linked to defects at distinct steps in pre-rRNA processing, which are outlined in Figure 1. 2 Several ribosomal proteins have extraribosomal functions, including replication and DNA repair, so mutations in ribosomal proteins may have effects that are independent of the protein translation machinery. 7,8 …”

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

“…Many reports proved that the errors of progress in the ribosomal biogenesis were the cause of the various diseases. The inherited bone marrow failure syndromes representatively showed a close relationship between p53-mediated cell growth regulation and cellular responses to abnormality of ribosome synthesis (Liu and Ellis, 2006). Interestingly, in zebrafish, it was suggested that aberrant ribosome biogenesis through the mutation of ribosomal genes has an oncogenic potential (Amsterdam et al, 2004).…”

PIM1 kinase is destabilized by ribosomal stress causing inhibition of cell cycle progression

“…This occurs, for example, in the case of conditional deletion of RPS6 (Volarevic et al, 2000;Sulic et al, 2005) or in response to drugs that disrupt nucleolar structures (Rubbi and Milner, 2003). Alteration of ribosome synthesis has also been implicated in some pathologies that are associated to mutations in ribosomal components, for instance, Diamond-Blackfan anemia (DBA), or in molecules involved in ribosome maturation (reviewed by Liu andEllis, 2006 andCaldarola et al, 2009).…”