Abstract
The autosomal recessive disorder Shwachman-Diamond syndrome, characterized by bone marrow failure and leukemia predisposition, is caused by deficiency of the highly conserved Shwachman-Bodian-Diamond syndrome (SBDS) protein. Here, we identify the function of the yeast SBDS ortholog Sdo1, showing that it is critical for the release and recycling of the nucleolar shuttling factor Tif6 from pre-60S ribosomes, a key step in 60S maturation and translational activation of ribosomes. Using genome-wide synthetic genetic array mapping, we identified multiple TIF6 gain-of-function alleles that suppressed the pre-60S nuclear export defects and cytoplasmic mislocalization of Tif6 observed in sdo1Delta cells. Sdo1 appears to function within a pathway containing elongation factor-like 1, and together they control translational activation of ribosomes. Thus, our data link defective late 60S ribosomal subunit maturation to an inherited bone marrow failure syndrome associated with leukemia predisposition.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Carrier Proteins / genetics
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GTP Phosphohydrolases / genetics
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GTP Phosphohydrolases / physiology
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Gene Deletion
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Intermediate Filament Proteins / genetics
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Models, Biological
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Models, Molecular
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Mutation
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Organisms, Genetically Modified
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Peptide Elongation Factors / genetics
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Peptide Elongation Factors / physiology
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Phosphoproteins / genetics
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Protein Biosynthesis / drug effects
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Protein Biosynthesis / genetics*
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Protein Synthesis Inhibitors / pharmacology
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Ribosomal Proteins
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Ribosomes / metabolism*
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Saccharomyces cerevisiae / genetics*
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Saccharomyces cerevisiae / growth & development
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Saccharomyces cerevisiae Proteins / genetics
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Saccharomyces cerevisiae Proteins / physiology*
Substances
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Carrier Proteins
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Intermediate Filament Proteins
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Peptide Elongation Factors
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Phosphoproteins
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Protein Synthesis Inhibitors
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Ribosomal Proteins
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Saccharomyces cerevisiae Proteins
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Sdo1 protein, S cerevisiae
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TIF6 protein, S cerevisiae
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GTP Phosphohydrolases
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RIA1 protein, S cerevisiae