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: 5.48). 12/2007; 21(13):3442-5. DOI: 10.1096/fj.07-8766hyp
Source: PubMed

ABSTRACT 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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    ABSTRACT: Diamond–Blackfan anemia (DBA) is a severe congenital anemia characterized by a specific decrease of erythroid precursors. The disease is also associated with growth retardation, congenital malformations, a predisposition for malignant disease and heterozygous mutations in either of the ribosomal protein (RP) genes RPS7, RPS17, RPS19, RPS24, RPL5, RPL11 and RPL35a. We show herein that primary fibroblasts from DBA patients with truncating mutations in RPS19 or in RPS24 have a marked reduction in proliferative capacity. Mutant fibroblasts are associated with extended cell cycles and normal levels of p53 when compared to w.t. cells. RPS19 mutant fibroblasts accumulate in the G1 phase, whereas the RPS24 mutant cells show an altered progression in the S phase resulting in reduced levels in the G2/M phase. RPS19 deficient cells exhibit reduced levels of Cyclin-E, CDK2 and retinoblastoma (Rb) protein supporting a cell cycle arrest in the G1 phase. In contrast, RPS24 deficient cells show increased levels of the cell cycle inhibitor p21 and a seemingly opposing increase in Cyclin-E, CDK4 and CDK6. In combination, our results show that RPS19 and RPS24 insufficient fibroblasts have an impaired growth caused by distinct blockages in the cell cycle. We suggest this proliferative constraint to be an important contributing mechanism for the complex extra-hematological features observed in DBA.
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