Ribosomal protein mutations in Diamond-Blackfan anemia: Might they operate upstream from protein synthesis?

Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 377 Plantation St., Worcester, MA 01605, USA.
The FASEB Journal (Impact Factor: 5.04). 12/2007; 21(13):3442-5. DOI: 10.1096/fj.07-8766hyp
Source: PubMed


The inherited bone marrow failure syndromes are clinically distinct but share some common features. Difficult to treat and typified by a poor prognosis, their pathogenesis is unknown. Recent findings that some patients with the erythroblastopenia Diamond-Blackfan anemia (DBA) have mutations in ribosomal proteins have led to the idea that this and perhaps other bone marrow failure disorders result from an inadequate supply of normally functioning ribosomes. According to this hypothesis, an insufficiency of the protein synthetic capacity limits the replicative potential of cells, with the DBA disease phenotype in particular arising from a block of one or more of the two to four critical, temporally compressed cell divisions in the differentiation program of the erythroid lineage in the fetal liver and the postnatal bone marrow. Here I propose an alternative (but not mutually exclusive) hypothesis centered on nucleoli: the specialized intranuclear domains within which ribosomes are assembled. It was recently discovered that the nucleoli contain cell cycle machinery in close proximity to nascent ribosomes. Although mutations in ribosomal proteins might be expected to negatively influence the cell's protein synthetic capacity, I suggest it is also possible that the DBA mutations directly affect the nucleolus to destabilize or otherwise deregulate the coresident cell cycle machinery. This hypothesis envisions that the ribosomal protein mutations discovered in DBA act upstream from ribosome assembly by interfering with the staging of cell cycle progression machinery in the nucleolus, in a pretranslational mode of pathogenesis.

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    • "A connection between the nucleolus and cell cycle had been described in early literature, where UV microbeam ablation of interphase nucleoli in grasshopper neuroblasts was observed to cause an arrest of mitosis that could not be explained simply on the basis of ribosome deficiency (Gaulden and Perry, 1958). This general notion has been more recently raised in connection with a human bone marrow failure disease (Pederson, 2007). Indeed, there is now a compelling body of evidence showing that eukaryotic cell cycle progression is not only associated with ribosome biosynthesis, but that the nucleolus may indeed be the central regulatory link between these two cellular activities. "
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    ABSTRACT: The life of the nucleolus has proven to be more colorful and multifaceted than had been envisioned a decade ago. A large number of proteins found in this subnuclear compartment have no identifiable tie either to the ribosome biosynthetic pathway or to the other newly established activities occurring within the nucleolus. The questions of how and why these proteins end up in this subnuclear compartment remain unanswered and are the focus of intense current interest. This review discusses our thoughts on the discovery of nonribosomal proteins in the nucleolus.
    Preview · Article · Apr 2009 · The Journal of Cell Biology
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    • ", 2005 ) . According to these data , Pederson ( 2007 ) proposed a hypothesis that disruption of normal ribosome assembly in the nucleolus triggers a direct negative effect on the coresident nonribosomal mechanisms , especially on the cell cycle machinery ( see also Dez and Tollervey , 2004 ) . It should be mentioned that the DFC also exhibit structure - function difference : fibrillarin , a specific marker of the DFC , is located close to r - genes during transcription , probably associated with nascent transcripts , but is located apart from the r - genes during their replication ( Raska et al . "
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    ABSTRACT: The nucleolus is a nuclear compartment and represents the most obvious and clearly differentiated nuclear structure seen in the microscope. Within nucleoli most events of ribosome biogenesis, such as ribosomal RNA synthesis, processing, and ribosome subunit assembly, take place. Several lines of evidence now show that the nucleolus has also numerous non-ribosomal functions. This review is focused on the recent progress in our knowledge of how to correlate the known biochemical processes taking place in the nucleolus with nucleolar structures observed in the microscope. We still lack detailed enough information to understand fully the organization and regulation of the processes taking place in the nucleolar sub-structures. However, the present power of microscopy techniques should allow for an in situ description of the organization of nucleolar processes at the molecular level in the years to come.
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    ABSTRACT: Impairment of ribosome biogenesis or function characterizes several of the inherited bone marrow failure syndromes: Diamond-Blackfan anaemia, dyskeratosis congenita (DC), Shwachman-Diamond syndrome and cartilage-hair hypoplasia. These syndromes exhibit overlapping but distinct clinical phenotypes and each disorder involves different aspects of ribosomal biogenesis. The clinical characteristics of each syndrome are briefly reviewed. Molecular studies of ribosome biogenesis and function in each of these syndromes are discussed. Models of how impairment of ribosomal pathways might affect haematopoiesis and tumorigenesis are explored.
    Preview · Article · Jun 2008 · British Journal of Haematology
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